https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Adekunle+OnipeProteopedia - User contributions [en]2026-09-21T09:23:48ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=User_talk:Adekunle_Onipe&diff=2498427User talk:Adekunle Onipe2015-11-23T02:42:59Z<p>Adekunle Onipe: User talk:Adekunle Onipe moved to Talk:Onipe, A.: Initials better</p>
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<div>#REDIRECT [[Talk:Onipe, A.]]</div>Adekunle Onipehttps://proteopedia.org/index.php?title=Talk:Onipe,_A.&diff=2498426Talk:Onipe, A.2015-11-23T02:42:59Z<p>Adekunle Onipe: User talk:Adekunle Onipe moved to Talk:Onipe, A.: Initials better</p>
<hr />
<div>'''Welcome to ''Proteopedia''!''' We hope you will contribute much and well. You will probably want to watch the narrated [[Proteopedia:Video_Guide|video guide]] and use the [[Help:Contents|help pages]] for later reference. Again, welcome and have fun! [[User:Jaime Prilusky|Jaime Prilusky]] 19:44, 21 June 2011 (IDT)</div>Adekunle Onipehttps://proteopedia.org/index.php?title=User:Adekunle_Onipe&diff=2498425User:Adekunle Onipe2015-11-23T02:42:59Z<p>Adekunle Onipe: User:Adekunle Onipe moved to Onipe, A.: Initials better</p>
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<div>#REDIRECT [[Onipe, A.]]</div>Adekunle Onipehttps://proteopedia.org/index.php?title=Onipe,_A.&diff=2498424Onipe, A.2015-11-23T02:42:59Z<p>Adekunle Onipe: User:Adekunle Onipe moved to Onipe, A.: Initials better</p>
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<div>'''Page Contributor & Editor''' <br />
----<br />
<br />
| [http://proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma Family]<br />
| [http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP LDB3/ZASP]<br />
| [http://proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin Myotilin]<br />
| [http://proteopedia.org/wiki/index.php/Group:MUZIC:ALP ALP]<br />
<br />
----</div>Adekunle Onipehttps://proteopedia.org/index.php?title=Onipe,_A.&diff=2498423Onipe, A.2015-11-23T02:24:54Z<p>Adekunle Onipe: </p>
<hr />
<div>'''Page Contributor & Editor''' <br />
----<br />
<br />
| [http://proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma Family]<br />
| [http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP LDB3/ZASP]<br />
| [http://proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin Myotilin]<br />
| [http://proteopedia.org/wiki/index.php/Group:MUZIC:ALP ALP]<br />
<br />
----</div>Adekunle Onipehttps://proteopedia.org/index.php?title=Onipe,_A.&diff=2498422Onipe, A.2015-11-23T02:22:33Z<p>Adekunle Onipe: </p>
<hr />
<div>'''Page Contributor & Editor''' <br />
----<br />
<br />
[http://proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma Family]<br />
[http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP LDB3/ZASP]<br />
[http://proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin Myotilin]<br />
[http://proteopedia.org/wiki/index.php/Group:MUZIC:ALP ALP]<br />
<br />
----</div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Enigma_Family&diff=2420127Group:MUZIC:Enigma Family2015-07-16T01:07:34Z<p>Adekunle Onipe: /* Pathology */</p>
<hr />
<div>==Introduction==<br />
<br />
'''Enigma subfamily: PDZ/LIM-domain proteins of the cytoskeleton'''. Three member proteins have extensively been described and characterized within this subfamily: '''Enigma''' protein, '''Enigma Homologue''' (ENH) protein and '''[http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP ZASP/Cypher/Oracle]''' (ZASP<ref>PMID:10427098</ref> being the human orthologue of cypher<ref>PMID:10391924</ref> in mouse, also identified by independent researchers as oracle<ref>PMID:10727866</ref>). The family name - ''Enigma'' - possibly was inspired by the intricately complicated splice variants identified in the first member, a common feature in all member proteins, as well as their redundant, indinstinct functions in the cytoskeleton. Didactically, protein members of the enigma subfamily typically possess within their structure: '''(1)''' an N-terminal PDZ domain (domain named after first three proteins where it was initially characterized i.e. '''P'''SD 95, '''D'''isc large protein and '''Z'''onula Occludens 1), and '''(2)''' three C-terminal LIM domains (domain named after three proteins where it was first characterized '''L'''in-11, '''I'''sl1 and '''M'''ec-3)<ref>PMID:20042479</ref>. The Enigma member proteins have all been located to the mammalian muscle cells, some specific to the heart and skeletal muscle Z-disk. They interact via their PDZ domains with protein components of the Z-disk and also recruit signalling molecules via their LIM domains or internal motifs, for example ''ZM motif'' (ZASP-like motif which is sandwiched between the PDZ- and LIM-domains in ZASP)<ref>doi:10.1161/CIRCRESAHA.110.225615</ref>. These interactions via their PDZ- and LIM-domains suggest roles important for targeting/sustaining interacting protein complexes within the myofibrillar sarcomere for a physiologically functional muscle.<br />
<br />
==Sequence annotation==<br />
<br />
[[Image:Enigma_family.png|left|thumb|450px| PDZ- and LIM-domains map in the first isoforms of human Enigma subfamily members: <br />
'''ZASP''' [http://www.uniprot.org/uniprot/O75112#section_features)]'''ENH''' [http://www.uniprot.org/uniprot/Q96HC4#section_alternative]'''Enigma''' [http://www.uniprot.org/uniprot/Q9NR12#section_features]]]<br />
<br />
'''[http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP ZASP]''' ('''Z'''-disk '''A'''lternatively '''S'''pliced '''P'''DZ domain protein), also referred to as LIM domain-binding protein 3 (LDB-3), is the 78 kDa, 727-amino-acid human ortholog of cypher, independently identified in heart and skeletal<br />
muscle<ref>PMID:10427098</ref>. Five alternatively spliced isoforms of ZASP have been identified (UniProtKB: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)]. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. <br />
<br />
'''Enigma Homologue (ENH)''' protein, also referred to as PDLIM5, is ~67 kDa, 596-amino-acid human ortholog of rat ENH<br />
protein <ref>PMID:10429367</ref> with four alternatively spliced isoforms (UniProtKB ID: Q96HC4)[http://www.uniprot.org/uniprot/Q96HC4#section_alternative].<br />
<br />
'''Enigma''' protein<br />
alternatively referred to as PDLIM7 (PDZ and LIM domain protein 7) is the first and representative member of the Enigma subfamily. Initially characterized in human as ~49.85 kDa, 457 amino-acid protein with an N-terminal PDZ domain and three C-terminal LIM domains <ref>PMID:7929196</ref> <ref>PMID:10359609</ref>. Five alternatively spliced isoforms are presently identified (UniProtKB ID: Q9NR12)[http://www.uniprot.org/uniprot/Q9NR12#section_features].<br />
<br />
==Structure==<br />
<br />
<Structure load='LIM1.pdb' size='200' frame='true' align='right' caption='NMR solution structure of LIM-1 domain of Enigma Homologue protein (PDB ID: 2DAR) [http://www.rcsb.org/pdb/explore/explore.do?structureId=2DAR]' scene='User:Adekunle_Onipe/workbench/Enigma_Family/Enh_lim1/2' /><br />
<br />
<Structure load='PDLIM7.pdb' size='200' frame='true' align='right' caption='X-ray crystal structure of PDZ domain of Enigma protein at 1.11Å (PDB ID: 2Q3G [http://www.rcsb.org/pdb/explore/explore.do?structureId=2Q3G]' scene='User:Adekunle_Onipe/workbench/Enigma_Family/Pdz_enigma/3'/><br />
<br />
'''Molecular structures''' of PDZ domain(s) of the three member proteins have recently been solved. Likewise, the LIM-1 domain of Enigma Homologue protein has yielded its structure in atomic details. Structural model of all member proteins reveal canonical PDZ domain fold containing six β-strands (A-F) and 2 α-helices (A and B) [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY]<br />
<br />
==Function and Interactions==<br />
In general, the PDZ domain(s) of Enigma subfamily have been structurally revealed as a classical<br />
class I PDZ domain - this is suggested by its interaction with<br />
the C-terminal region of α-actinin-2 <ref>PMID:15062084</ref>. Recently, it has been shown that the PDZ domains of Enigma subfamily proteins<br />
also interacts with Myotilin and Calsarcin/FATZ C-terminal<br />
motifs, which have the characteristics of class III PDZ-binding<br />
domain sequences <ref>PMID:19047374</ref>. Moreover, the LIM domain(s) of Enigma subfamily proteins interact<br />
with different domains in various proteins, particularly in signaling<br />
factors. This common structural feature supports the notion that Enigma proteins serve as adaptor proteins, where the<br />
PDZ domain tethers the protein to the cytoskeleton and the LIM<br />
domain or additional internal domains (ZM-motif), recruit signaling proteins to implement corresponding functions (see <ref>doi:10.1093/jmcb/mjp038</ref>, and references therein). In addition, experimental evidences indicate Enigma protein may function as a scaffold on which the coordinated assembly of sarcomeric proteins can occur; largely owing to the interactions via its PDZ- and LIM domains with actin-associated proteins of cardiac and skeletal muscle, as well as non-muscle tissues [[<ref>PMID:7929196</ref>]]. It has also been implicated in bone formation and fracture repair<ref>PMID:11874232</ref>. It may also be involved in BMP6 signaling pathway. Generally, it interacts with various PKC isoforms using the LIM domains<ref>PMID:8940095</ref>. The LIM-2 domain has been shown to interact with TBX4, as well as RET in a phosphorylation-independent manner<ref>PMID:9528800</ref>. Despite the co-localization of '''Enigma protein''' with proteins in the Z-line and I-band, a definite functional role in the sarcomere has not<br />
been shown yet<ref>doi:10.1093/jmcb/mjp038</ref>; '''''which resounds the literal meaning of the word Enigma'''.''<br />
<br />
==Pathology==<br />
Mutations in the '''[http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP ZASP]''' gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular noncompaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. Recently, mutations in ZASP have been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. The expression studies of Maeno-Hikichi et al., who found the '''ENH protein''' expressed in<br />
various regions of the brain, suggest a possible role in brain development<ref>PMID:12665800</ref>. In accordance, ENH<br />
expression levels were found to be significantly increased in all brain regions of patients with bipolar disorder, schizophrenia, and major depression(see <ref>DOI 10.1100/tsw.2007.232</ref>, and references therein).<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Onipe,_A.&diff=2420126Onipe, A.2015-07-16T00:57:45Z<p>Adekunle Onipe: </p>
<hr />
<div>'''PhD, University of Vienna''' | <br />
Page Contributor & Editor<br />
----<br />
<br />
[http://proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma Family]<br />
[http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP LDB3/ZASP]<br />
[http://proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin Myotilin]<br />
[http://proteopedia.org/wiki/index.php/Group:MUZIC:ALP ALP]<br />
<br />
----</div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Enigma_Family&diff=2420125Group:MUZIC:Enigma Family2015-07-16T00:21:44Z<p>Adekunle Onipe: </p>
<hr />
<div>==Introduction==<br />
<br />
'''Enigma subfamily: PDZ/LIM-domain proteins of the cytoskeleton'''. Three member proteins have extensively been described and characterized within this subfamily: '''Enigma''' protein, '''Enigma Homologue''' (ENH) protein and '''[http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP ZASP/Cypher/Oracle]''' (ZASP<ref>PMID:10427098</ref> being the human orthologue of cypher<ref>PMID:10391924</ref> in mouse, also identified by independent researchers as oracle<ref>PMID:10727866</ref>). The family name - ''Enigma'' - possibly was inspired by the intricately complicated splice variants identified in the first member, a common feature in all member proteins, as well as their redundant, indinstinct functions in the cytoskeleton. Didactically, protein members of the enigma subfamily typically possess within their structure: '''(1)''' an N-terminal PDZ domain (domain named after first three proteins where it was initially characterized i.e. '''P'''SD 95, '''D'''isc large protein and '''Z'''onula Occludens 1), and '''(2)''' three C-terminal LIM domains (domain named after three proteins where it was first characterized '''L'''in-11, '''I'''sl1 and '''M'''ec-3)<ref>PMID:20042479</ref>. The Enigma member proteins have all been located to the mammalian muscle cells, some specific to the heart and skeletal muscle Z-disk. They interact via their PDZ domains with protein components of the Z-disk and also recruit signalling molecules via their LIM domains or internal motifs, for example ''ZM motif'' (ZASP-like motif which is sandwiched between the PDZ- and LIM-domains in ZASP)<ref>doi:10.1161/CIRCRESAHA.110.225615</ref>. These interactions via their PDZ- and LIM-domains suggest roles important for targeting/sustaining interacting protein complexes within the myofibrillar sarcomere for a physiologically functional muscle.<br />
<br />
==Sequence annotation==<br />
<br />
[[Image:Enigma_family.png|left|thumb|450px| PDZ- and LIM-domains map in the first isoforms of human Enigma subfamily members: <br />
'''ZASP''' [http://www.uniprot.org/uniprot/O75112#section_features)]'''ENH''' [http://www.uniprot.org/uniprot/Q96HC4#section_alternative]'''Enigma''' [http://www.uniprot.org/uniprot/Q9NR12#section_features]]]<br />
<br />
'''[http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP ZASP]''' ('''Z'''-disk '''A'''lternatively '''S'''pliced '''P'''DZ domain protein), also referred to as LIM domain-binding protein 3 (LDB-3), is the 78 kDa, 727-amino-acid human ortholog of cypher, independently identified in heart and skeletal<br />
muscle<ref>PMID:10427098</ref>. Five alternatively spliced isoforms of ZASP have been identified (UniProtKB: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)]. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. <br />
<br />
'''Enigma Homologue (ENH)''' protein, also referred to as PDLIM5, is ~67 kDa, 596-amino-acid human ortholog of rat ENH<br />
protein <ref>PMID:10429367</ref> with four alternatively spliced isoforms (UniProtKB ID: Q96HC4)[http://www.uniprot.org/uniprot/Q96HC4#section_alternative].<br />
<br />
'''Enigma''' protein<br />
alternatively referred to as PDLIM7 (PDZ and LIM domain protein 7) is the first and representative member of the Enigma subfamily. Initially characterized in human as ~49.85 kDa, 457 amino-acid protein with an N-terminal PDZ domain and three C-terminal LIM domains <ref>PMID:7929196</ref> <ref>PMID:10359609</ref>. Five alternatively spliced isoforms are presently identified (UniProtKB ID: Q9NR12)[http://www.uniprot.org/uniprot/Q9NR12#section_features].<br />
<br />
==Structure==<br />
<br />
<Structure load='LIM1.pdb' size='200' frame='true' align='right' caption='NMR solution structure of LIM-1 domain of Enigma Homologue protein (PDB ID: 2DAR) [http://www.rcsb.org/pdb/explore/explore.do?structureId=2DAR]' scene='User:Adekunle_Onipe/workbench/Enigma_Family/Enh_lim1/2' /><br />
<br />
<Structure load='PDLIM7.pdb' size='200' frame='true' align='right' caption='X-ray crystal structure of PDZ domain of Enigma protein at 1.11Å (PDB ID: 2Q3G [http://www.rcsb.org/pdb/explore/explore.do?structureId=2Q3G]' scene='User:Adekunle_Onipe/workbench/Enigma_Family/Pdz_enigma/3'/><br />
<br />
'''Molecular structures''' of PDZ domain(s) of the three member proteins have recently been solved. Likewise, the LIM-1 domain of Enigma Homologue protein has yielded its structure in atomic details. Structural model of all member proteins reveal canonical PDZ domain fold containing six β-strands (A-F) and 2 α-helices (A and B) [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY]<br />
<br />
==Function and Interactions==<br />
In general, the PDZ domain(s) of Enigma subfamily have been structurally revealed as a classical<br />
class I PDZ domain - this is suggested by its interaction with<br />
the C-terminal region of α-actinin-2 <ref>PMID:15062084</ref>. Recently, it has been shown that the PDZ domains of Enigma subfamily proteins<br />
also interacts with Myotilin and Calsarcin/FATZ C-terminal<br />
motifs, which have the characteristics of class III PDZ-binding<br />
domain sequences <ref>PMID:19047374</ref>. Moreover, the LIM domain(s) of Enigma subfamily proteins interact<br />
with different domains in various proteins, particularly in signaling<br />
factors. This common structural feature supports the notion that Enigma proteins serve as adaptor proteins, where the<br />
PDZ domain tethers the protein to the cytoskeleton and the LIM<br />
domain or additional internal domains (ZM-motif), recruit signaling proteins to implement corresponding functions (see <ref>doi:10.1093/jmcb/mjp038</ref>, and references therein). In addition, experimental evidences indicate Enigma protein may function as a scaffold on which the coordinated assembly of sarcomeric proteins can occur; largely owing to the interactions via its PDZ- and LIM domains with actin-associated proteins of cardiac and skeletal muscle, as well as non-muscle tissues [[<ref>PMID:7929196</ref>]]. It has also been implicated in bone formation and fracture repair<ref>PMID:11874232</ref>. It may also be involved in BMP6 signaling pathway. Generally, it interacts with various PKC isoforms using the LIM domains<ref>PMID:8940095</ref>. The LIM-2 domain has been shown to interact with TBX4, as well as RET in a phosphorylation-independent manner<ref>PMID:9528800</ref>. Despite the co-localization of '''Enigma protein''' with proteins in the Z-line and I-band, a definite functional role in the sarcomere has not<br />
been shown yet<ref>doi:10.1093/jmcb/mjp038</ref>; '''''which resounds the literal meaning of the word Enigma'''.''<br />
<br />
==Pathology==<br />
Mutations in the '''ZASP''' gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular noncompaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. Recently, mutations in ZASP have been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. The expression studies of Maeno-Hikichi et al., who found the '''ENH protein''' expressed in<br />
various regions of the brain, suggest a possible role in brain development<ref>PMID:12665800</ref>. In accordance, ENH<br />
expression levels were found to be significantly increased in all brain regions of patients with bipolar disorder, schizophrenia, and major depression(see <ref>DOI 10.1100/tsw.2007.232</ref>, and references therein).<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Onipe,_A.&diff=2370442Onipe, A.2015-02-06T02:52:29Z<p>Adekunle Onipe: </p>
<hr />
<div>doctoral in structural biology, University of Vienna.</div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1746563Group:MUZIC:ZASP2013-03-22T14:17:30Z<p>Adekunle Onipe: /* Function and Interactions */</p>
<hr />
<div>== Introduction==<br />
The '''Z'''-disc '''A'''lternatively '''S'''pliced '''P'''DZ-domain containing ('''ZASP''') protein, also referred to as LIM domain-binding protein 3 (LDB-3), is a 78 kDa, 727-amino-acid human ortholog of cypher (in mouse), independently located to striated heart and skeletal muscle cells<ref>PMID:10427098</ref>, as well as integrin adhesion sites in insect tissues<ref name="dp">doi: 10.1083/jcb.200707045</ref>. ZASP is a major component protein of the striated muscle Z-disc and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has been recently reported to interact with the PDZ-binding motifs in [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:actinin2 α-actinin-2], [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin]<ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers complementary interacting capabilities<ref name="xp">doi:10.1016/j.yexcr.2005.12.036</ref>. Together, these suggest ZASP plays an important role during myofibrillogenesis and the assembly of multi-protein complexes in muscle Z-discs as well as integrin adhesion sites <ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
<br />
[[Image:zasp-new.png|left|400px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==Structure==<br />
The solution structure of ZASP PDZ domain revealed a canonical PDZ domain fold containing six β-strands and two α-helices in a circular permutation mode common to PDZ domains<ref>PMID:15062084</ref>. The structure of ZASP LIM domain(s) is presently unknown, neither is there an experimental structure for ZASP PDZ domain fused with one or two of its binding partners <Structure load='1rgw' size='300' frame='true' align='right' caption= 'NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: [[1rgw]]) [http://www.rcsb.org/pdb/explore/explore.do?structureId=1rgw]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3'/>.<br />
<br />
==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the '''oracle''' of Z-disk multi-protein complexes by tethering and regulating interacting proteins via its PDZ and LIM domains. This is suggested by experimental evidences which show the PDZ domain of ZASP interacts with myotilin, FATZ protein family and α-actinin-2. Based on interaction with the class I PDZ-binding motif (PBM) of α-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. A recent report on the interaction of ZASP PDZ domain with class III PBMs in myotilin and myozenin suggests that ZASP PDZ domain has dual capacity (or classification) and possible structural plasticity as it is able to bind both class I and class III motifs<ref name="b" /> from three different proteins. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref name= "xp">doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
<br />
==Pathology==<br />
Muscle disorders resulting from aberration(s) in ZASP gene are described as ZASPopathies<ref>doi: 10.1093/brain/awm006</ref>.<br />
Mutations in the ZASP gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular non-compaction of the myocardium (INLVM) in humans<ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. ZASP as also been shown to be the major Z-disc component to have O-linked-β-N-acetylglucosamine; (O-GlcNAc) modification, with significant modification in diseased states<ref>PMID: 23271734</ref>; this possibly presents ZASP as a prominent marker of cardiac dysfunction with diagnostic importance. Mutations in ZASP have recently been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganised and<br />
fragmented Z-lines in skeletal and cardiac muscle<ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>. Similarly, dis-organisation of integrin-adhesion sites was observed in insect tissues lacking in ZASP<ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1746562Group:MUZIC:ZASP2013-03-22T14:16:57Z<p>Adekunle Onipe: /* Introduction */</p>
<hr />
<div>== Introduction==<br />
The '''Z'''-disc '''A'''lternatively '''S'''pliced '''P'''DZ-domain containing ('''ZASP''') protein, also referred to as LIM domain-binding protein 3 (LDB-3), is a 78 kDa, 727-amino-acid human ortholog of cypher (in mouse), independently located to striated heart and skeletal muscle cells<ref>PMID:10427098</ref>, as well as integrin adhesion sites in insect tissues<ref name="dp">doi: 10.1083/jcb.200707045</ref>. ZASP is a major component protein of the striated muscle Z-disc and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has been recently reported to interact with the PDZ-binding motifs in [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:actinin2 α-actinin-2], [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin]<ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers complementary interacting capabilities<ref name="xp">doi:10.1016/j.yexcr.2005.12.036</ref>. Together, these suggest ZASP plays an important role during myofibrillogenesis and the assembly of multi-protein complexes in muscle Z-discs as well as integrin adhesion sites <ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
<br />
[[Image:zasp-new.png|left|400px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==Structure==<br />
The solution structure of ZASP PDZ domain revealed a canonical PDZ domain fold containing six β-strands and two α-helices in a circular permutation mode common to PDZ domains<ref>PMID:15062084</ref>. The structure of ZASP LIM domain(s) is presently unknown, neither is there an experimental structure for ZASP PDZ domain fused with one or two of its binding partners <Structure load='1rgw' size='300' frame='true' align='right' caption= 'NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: [[1rgw]]) [http://www.rcsb.org/pdb/explore/explore.do?structureId=1rgw]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3'/>.<br />
<br />
==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the '''oracle''' of Z-disk multi-protein complexes by tethering and regulating interacting proteins via its PDZ and LIM domains. This is suggested by experimental evidences which show the PDZ domain of ZASP interacts with myotilin, FATZ protein family and α-actinin-2. Based on interaction with the class I PDZ-binding motif (PBM) of α-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. A recent report on the interaction of ZASP PDZ domain with class III PBMs in myotilin and myozenin suggests that ZASP PDZ domain has dual capacity (or classification) and possible structural plasticity as it is able to bind both class I and class III motifs<ref name="b" /> from three different proteins. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
<br />
==Pathology==<br />
Muscle disorders resulting from aberration(s) in ZASP gene are described as ZASPopathies<ref>doi: 10.1093/brain/awm006</ref>.<br />
Mutations in the ZASP gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular non-compaction of the myocardium (INLVM) in humans<ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. ZASP as also been shown to be the major Z-disc component to have O-linked-β-N-acetylglucosamine; (O-GlcNAc) modification, with significant modification in diseased states<ref>PMID: 23271734</ref>; this possibly presents ZASP as a prominent marker of cardiac dysfunction with diagnostic importance. Mutations in ZASP have recently been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganised and<br />
fragmented Z-lines in skeletal and cardiac muscle<ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>. Similarly, dis-organisation of integrin-adhesion sites was observed in insect tissues lacking in ZASP<ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1746561Group:MUZIC:ZASP2013-03-22T10:34:38Z<p>Adekunle Onipe: /* Introduction */</p>
<hr />
<div>== Introduction==<br />
The '''Z'''-disc '''A'''lternatively '''S'''pliced '''P'''DZ-domain containing ('''ZASP''') protein, also referred to as LIM domain-binding protein 3 (LDB-3), is a 78 kDa, 727-amino-acid human ortholog of cypher (in mouse), independently located to striated heart and skeletal muscle cells<ref>PMID:10427098</ref>, as well as integrin adhesion sites in insect tissues<ref name="dp">doi: 10.1083/jcb.200707045</ref>. ZASP is a major component protein of the striated muscle Z-disc and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has been recently reported to interact with the PDZ-binding motifs in [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:actinin2 α-actinin-2], [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin]<ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers complementary interacting capabilities<ref>doi:10.1016/j.yexcr.2005.12.036</ref>. Together, these suggest ZASP plays an important role during myofibrillogenesis and the assembly of multi-protein complexes in muscle Z-discs as well as integrin adhesion sites <ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
<br />
[[Image:zasp-new.png|left|400px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==Structure==<br />
The solution structure of ZASP PDZ domain revealed a canonical PDZ domain fold containing six β-strands and two α-helices in a circular permutation mode common to PDZ domains<ref>PMID:15062084</ref>. The structure of ZASP LIM domain(s) is presently unknown, neither is there an experimental structure for ZASP PDZ domain fused with one or two of its binding partners <Structure load='1rgw' size='300' frame='true' align='right' caption= 'NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: [[1rgw]]) [http://www.rcsb.org/pdb/explore/explore.do?structureId=1rgw]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3'/>.<br />
<br />
==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the '''oracle''' of Z-disk multi-protein complexes by tethering and regulating interacting proteins via its PDZ and LIM domains. This is suggested by experimental evidences which show the PDZ domain of ZASP interacts with myotilin, FATZ protein family and α-actinin-2. Based on interaction with the class I PDZ-binding motif (PBM) of α-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. A recent report on the interaction of ZASP PDZ domain with class III PBMs in myotilin and myozenin suggests that ZASP PDZ domain has dual capacity (or classification) and possible structural plasticity as it is able to bind both class I and class III motifs<ref name="b" /> from three different proteins. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
<br />
==Pathology==<br />
Muscle disorders resulting from aberration(s) in ZASP gene are described as ZASPopathies<ref>doi: 10.1093/brain/awm006</ref>.<br />
Mutations in the ZASP gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular non-compaction of the myocardium (INLVM) in humans<ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. ZASP as also been shown to be the major Z-disc component to have O-linked-β-N-acetylglucosamine; (O-GlcNAc) modification, with significant modification in diseased states<ref>PMID: 23271734</ref>; this possibly presents ZASP as a prominent marker of cardiac dysfunction with diagnostic importance. Mutations in ZASP have recently been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganised and<br />
fragmented Z-lines in skeletal and cardiac muscle<ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>. Similarly, dis-organisation of integrin-adhesion sites was observed in insect tissues lacking in ZASP<ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1745070Group:MUZIC:ALP2013-03-19T11:10:58Z<p>Adekunle Onipe: /* Function and Interactions */</p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in vertebrates. Protein members of this subfamily include: '''CLP36''' (also known as PDLIM1 or hCLIM1 (in human)<ref>PMID:10022510</ref> and Elfin (in mouse)<ref>PMID:11596114</ref>), '''Mystique''' (aka PDLIM2 or SLIM)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>, '''ALP''' (aka PDLIM3)<ref name="r1">PMID:9334352</ref> and '''RIL''' (aka PDLIM4).<br />
<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.<br />
<br />
hCLIM1/CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref> which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|400px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
<br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4 is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently known (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Structures ==<br />
Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu viral particle (the PDZ-binding motif), shows structural mechanism of binding with atomic specificity <ref name="e">doi:10.1371/journal.pone.0019511</ref>. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.<br />
<Structure load='2PKT' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human hCLIM1 in complex with the C-terminal peptide of α-actinin-1 (PDB code: [[2pkt]])[http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT]'/><br />
<Structure load='3PDV' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human PDLIM2 in complex with pathogenic bird flu viral peptide NS1 (PDB code: [[3pdv]])[http://www.pdb.org/pdb/explore/explore.do?structureId=3PDV]'/><br />
<Structure load='1X64' size='150' frame='true' align='right' caption='NMR solution structure of the LIM domain of mouse PDLIM3 (ALP) (PDB code: [[1x64]])[http://www.pdb.org/pdb/explore/explore.do?structureId=1X64]'/><br />
<Structure load='1v51' size='150' frame='true' align='right' caption='NMR solution structure of the PDZ domain of mouse PDLIM3 (ALP) (PDB code: [[1v51]])[http://www.rcsb.org/pdb/explore/explore.do?pdbId=1v5l]'/><br />
<Structure load='2V1W' size='150' frame='true' align='right' caption='X-ray crystal stucture of the PDZ domain of human PDLIM4 (RIL) in complex with human α-actinin-1C-terminal peptide (PDB code: [[2v1w]])[http://www.rcsb.org/pdb/explore/explore.do?structureId=2V1W]'/><br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin. Interestingly, a non-structural interacting partner has recently been identified; the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus (NS1) peptide<ref name="e">doi:10.1371/journal.pone.0019511</ref>. An elegant summary of other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M ''et al'' (2010) <ref name="c">doi:10.1093/jmcb/mjp038</ref> and te Velthius A.J. ''et al'' (2007) <ref name="d">DOI 10.1100/tsw.2007.232</ref>.<br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been identified within the ALP subfamily<ref name="d">DOI 10.1100/tsw.2007.232</ref>, <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Human PDLIM2 (mystique) selectively interacts with highly pathogenic bird flu virus strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic viral protein to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the bird flu virus.<br />
<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1745069Group:MUZIC:ALP2013-03-19T11:08:48Z<p>Adekunle Onipe: /* Introduction */</p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in vertebrates. Protein members of this subfamily include: '''CLP36''' (also known as PDLIM1 or hCLIM1 (in human)<ref>PMID:10022510</ref> and Elfin (in mouse)<ref>PMID:11596114</ref>), '''Mystique''' (aka PDLIM2 or SLIM)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>, '''ALP''' (aka PDLIM3)<ref name="r1">PMID:9334352</ref> and '''RIL''' (aka PDLIM4).<br />
<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.<br />
<br />
hCLIM1/CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref> which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|400px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
<br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4 is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently known (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Structures ==<br />
Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu viral particle (the PDZ-binding motif), shows structural mechanism of binding with atomic specificity <ref name="e">doi:10.1371/journal.pone.0019511</ref>. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.<br />
<Structure load='2PKT' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human hCLIM1 in complex with the C-terminal peptide of α-actinin-1 (PDB code: [[2pkt]])[http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT]'/><br />
<Structure load='3PDV' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human PDLIM2 in complex with pathogenic bird flu viral peptide NS1 (PDB code: [[3pdv]])[http://www.pdb.org/pdb/explore/explore.do?structureId=3PDV]'/><br />
<Structure load='1X64' size='150' frame='true' align='right' caption='NMR solution structure of the LIM domain of mouse PDLIM3 (ALP) (PDB code: [[1x64]])[http://www.pdb.org/pdb/explore/explore.do?structureId=1X64]'/><br />
<Structure load='1v51' size='150' frame='true' align='right' caption='NMR solution structure of the PDZ domain of mouse PDLIM3 (ALP) (PDB code: [[1v51]])[http://www.rcsb.org/pdb/explore/explore.do?pdbId=1v5l]'/><br />
<Structure load='2V1W' size='150' frame='true' align='right' caption='X-ray crystal stucture of the PDZ domain of human PDLIM4 (RIL) in complex with human α-actinin-1C-terminal peptide (PDB code: [[2v1w]])[http://www.rcsb.org/pdb/explore/explore.do?structureId=2V1W]'/><br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin. Interestingly, a non-structural interacting partner as recently been identified; the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus (NS1) peptide<ref name="e">doi:10.1371/journal.pone.0019511</ref>. An elegant summary of other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M ''et al'' (2010) <ref name="c">doi:10.1093/jmcb/mjp038</ref> and te Velthius A.J. ''et al'' (2007) <ref name="d">DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been identified within the ALP subfamily<ref name="d">DOI 10.1100/tsw.2007.232</ref>, <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Human PDLIM2 (mystique) selectively interacts with highly pathogenic bird flu virus strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic viral protein to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the bird flu virus.<br />
<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1719026Group:MUZIC:Myotilin2013-02-07T12:24:36Z<p>Adekunle Onipe: /* Function and Interactions */</p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with a size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin (Ig)-like domains and a short C-terminal tail containing PDZ-binding motif (PBM).<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
<br />
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<br />
<br />
== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin(Ig)-like domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold <ref>PMID: 19466753</ref>.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
<br />
== Function and Interactions ==<br />
<br />
Myotilin participates in a network of multi-protein interactions within the sarcomere, mainly via its Ig-domains, and both N- and C-termini. All myotilin binding partners are components of [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Interactome the Z-disc] including '''actin''' (binds via its Ig-domains)<ref>PMID:16122733</ref>; '''α-actinin-2''' (binds via a 17-amino acid region on its N-terminal half which shares high degree of homology with palladin α-actinin-2 binding region<ref> doi:10.1016/j.jmb.2011.08.059 </ref> <ref name="a" />; '''filamin C''' (binds via the Ig-domains) <ref name="e">PMID: 11038172</ref>; '''FATZ-1''' (via the Ig-domains)<ref name="c">PMID: 16076904</ref> and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:ZASP ZASP] (binds via its C-terminal class III PDZ-binding motif)<ref name="d">PMID:19047374</ref>. Myotilin forms homodimer and efficiently cross-links actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle. The muscle quality control proteins localised to the Z-discs ('''MuRF3 and MuRF1''')<ref>PMID: 16337382</ref> have also been shown to interact with myotilin. The appearance of myotilin with α-actinin-2 in Z-bodies of premyofibrils (at the very early stage of myofibre development) suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Similarly, upregulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
<br />
== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathies <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutations, mostly in the N-terminal serine-rich part of the protein, cause the onset of most disorders <ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
<br />
== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1719024Group:MUZIC:Myotilin2013-02-07T12:21:38Z<p>Adekunle Onipe: /* Function and Interactions */</p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with a size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin (Ig)-like domains and a short C-terminal tail containing PDZ-binding motif (PBM).<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
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<br />
<br />
== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin(Ig)-like domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold <ref>PMID: 19466753</ref>.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
<br />
== Function and Interactions ==<br />
<br />
Myotilin participates in a network of multi-protein interactions within the sarcomere, mainly via its Ig-domains, and both N and C-termini. All myotilin binding partners are components of [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Interactome the Z-disc] including '''actin''' (binds via its Ig-domains),<ref>PMID:16122733</ref>; '''α-actinin-2''' (binds via a 17-amino acid region on its N-terminal half which shares high degree of homology with palladin α-actinin-2 binding region<ref> doi:10.1016/j.jmb.2011.08.059 </ref> <ref name="a" />; '''filamin C''' (binds via the Ig-domains) <ref name="e">PMID: 11038172</ref>; '''FATZ-1''' (via the Ig-domains)<ref name="c">PMID: 16076904</ref> and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:ZASP ZASP] (binds via its C-terminal class III PDZ-binding motif)<ref name="d">PMID:19047374</ref>. Myotilin forms homodimer and efficiently cross-links actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle. The muscle quality control proteins localised to the Z-discs ('''MuRF3 and MuRF1''')<ref>PMID: 16337382</ref> have also been shown to interact with myotilin. The appearance of myotilin with α-actinin-2 in Z-bodies of premyofibrils (at the very early stage of myofibre development) suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Similarly, upregulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
<br />
== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathies <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutations, mostly in the N-terminal serine-rich part of the protein, cause the onset of most disorders <ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
<br />
== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1719023Group:MUZIC:Myotilin2013-02-07T12:12:36Z<p>Adekunle Onipe: /* Function and Interactions */</p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with a size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin (Ig)-like domains and a short C-terminal tail containing PDZ-binding motif (PBM).<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
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<br />
== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin(Ig)-like domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold <ref>PMID: 19466753</ref>.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
<br />
== Function and Interactions ==<br />
<br />
Myotilin participates in a network of multi-protein interactions within the sarcomere, mainly via its Ig-domains, and both N and C-termini. All myotilin binding partners are components of [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Interactome the Z-disc] including '''actin''' (binds via its Ig-domains),<ref>PMID:16122733</ref> '''α-actinin-2''' (binds via a 17-amino acid region on its N-terminal half which shares high degree of homology with palladin α-actinin-2 binding region<ref> doi:10.1016/j.jmb.2011.08.059 </ref>,<ref name="a" /> '''filamin C''' (binds via the Ig-domains) <ref name="e">PMID: 11038172</ref>, '''FATZ-1''' (via the Ig-domains)<ref name="c">PMID: 16076904</ref> and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:ZASP '''ZASP'''] (binds via its C-terminal class III PDZ-binding motif)<ref name="d">PMID:19047374</ref>. The α-actinin-2 interaction site in myotilin sharesinteraction regionMyotilin forms homodimer and efficiently cross-links actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle. The muscle quality control proteins localised to the Z-discs ('''MuRF3 and MuRF1''')<ref>PMID: 16337382</ref> have also been shown to interact with myotilin. <br />
The appearance of myotilin with α-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Upregulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
<br />
== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathies <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutations, mostly in the N-terminal serine-rich part of the protein, cause the onset of most disorders <ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
<br />
== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1715571Group:MUZIC:ZASP2013-02-04T21:23:04Z<p>Adekunle Onipe: </p>
<hr />
<div>== Introduction==<br />
The '''Z'''-disc '''A'''lternatively '''S'''pliced '''P'''DZ-domain containing ('''ZASP''') protein, also referred to as LIM domain-binding protein 3 (LDB-3), is a 78 kDa, 727-amino-acid human ortholog of cypher (in mouse), independently located to striated heart and skeletal muscle cells<ref>PMID:10427098</ref>, as well as integrin adhesion sites in insect tissues<ref name="dp">doi: 10.1083/jcb.200707045</ref>. ZASP is a major component protein of the striated muscle Z-disc and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has been recently reported to interact with the PDZ-binding motifs in α-actinin-2, [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin]<ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers complementary interacting capabilities<ref>doi:10.1016/j.yexcr.2005.12.036</ref>. Together, these suggest ZASP plays an important role during myofibrillogenesis and the assembly of multi-protein complexes in muscle Z-discs as well as integrin adhesion sites <ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
<br />
[[Image:zasp-new.png|left|400px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
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==Structure==<br />
The solution structure of ZASP PDZ domain revealed a canonical PDZ domain fold containing six β-strands and two α-helices in a circular permutation mode common to PDZ domains<ref>PMID:15062084</ref>. The structure of ZASP LIM domain(s) is presently unknown, neither is there an experimental structure for ZASP PDZ domain fused with one or two of its binding partners <Structure load='1rgw' size='300' frame='true' align='right' caption= 'NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: 1RGW) [http://www.rcsb.org/pdb/explore/explore.do?structureId=1RGW]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3'/>.<br />
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==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the '''oracle''' of Z-disk multi-protein complexes by tethering and regulating interacting proteins via its PDZ and LIM domains. This is suggested by experimental evidences which show the PDZ domain of ZASP interacts with myotilin, FATZ protein family and α-actinin-2. Based on interaction with the class I PDZ-binding motif (PBM) of α-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. A recent report on the interaction of ZASP PDZ domain with class III PBMs in myotilin and myozenin suggests that ZASP PDZ domain has dual capacity (or classification) and possible structural plasticity as it is able to bind both class I and class III motifs<ref name="b" /> from three different proteins. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
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==Pathology==<br />
Muscle disorders resulting from aberration(s) in ZASP gene are described as ZASPopathies<ref>doi: 10.1093/brain/awm006</ref>.<br />
Mutations in the ZASP gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular non-compaction of the myocardium (INLVM) in humans<ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. ZASP as also been shown to be the major Z-disc component to have O-linked-β-N-acetylglucosamine; (O-GlcNAc) modification, with significant modification in diseased states<ref>PMID: 23271734</ref>; this possibly presents ZASP as a prominent marker of cardiac dysfunction with diagnostic importance. Mutations in ZASP have recently been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganised and<br />
fragmented Z-lines in skeletal and cardiac muscle<ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>. Similarly, dis-organisation of integrin-adhesion sites was observed in insect tissues lacking in ZASP<ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1715570Group:MUZIC:ALP2013-02-04T21:03:53Z<p>Adekunle Onipe: </p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in mammals. Protein members of this subfamily include: '''CLP36''' (also known as PDLIM1 or hCLIM1 (in human)<ref>PMID:10022510</ref> and Elfin (in mouse)<ref>PMID:11596114</ref>), '''Mystique''' (aka PDLIM2 or SLIM)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>, '''ALP''' (aka PDLIM3)<ref name="r1">PMID:9334352</ref> and '''RIL''' (aka PDLIM4).<br />
<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.<br />
<br />
hCLIM1/CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref> which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|400px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
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'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
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'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4 is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently known (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
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== Structures ==<br />
Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu viral particle (the PDZ-binding motif), shows structural mechanism of binding with atomic specificity <ref name="e">doi:10.1371/journal.pone.0019511</ref>. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.<br />
<Structure load='2PKT' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human hCLIM1 in complex with the C-terminal peptide of α-actinin-1 (PDB code: 2PKT)[http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT]'/><br />
<Structure load='3PDV' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human PDLIM2 in complex with pathogenic bird flu viral peptide NS1 (PDB code: 3PDV)[http://www.pdb.org/pdb/explore/explore.do?structureId=3PDV]'/><br />
<Structure load='1X64' size='150' frame='true' align='right' caption='NMR solution structure of the LIM domain of mouse PDLIM3 (ALP) (PDB code: 1X64)[http://www.pdb.org/pdb/explore/explore.do?structureId=1X64]'/><br />
<Structure load='1v51' size='150' frame='true' align='right' caption='NMR solution structure of the PDZ domain of mouse PDLIM3 (ALP) (PDB code: 1v51)[http://www.rcsb.org/pdb/explore/explore.do?pdbId=1v5l]'/><br />
<Structure load='2V1W' size='150' frame='true' align='right' caption='X-ray crystal stucture of the PDZ domain of human PDLIM4 (RIL) in complex with human α-actinin-1C-terminal peptide (PDB code: 2V1W)[http://www.rcsb.org/pdb/explore/explore.do?structureId=2V1W]'/><br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin. Interestingly, a non-structural interacting partner as recently been identified; the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus (NS1) peptide<ref name="e">doi:10.1371/journal.pone.0019511</ref>. An elegant summary of other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M ''et al'' (2010) <ref name="c">doi:10.1093/jmcb/mjp038</ref> and te Velthius A.J. ''et al'' (2007) <ref name="d">DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been identified within the ALP subfamily<ref name="d">DOI 10.1100/tsw.2007.232</ref>, <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Human PDLIM2 (mystique) selectively interacts with highly pathogenic bird flu virus strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic viral protein to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the bird flu virus.<br />
<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1715569Group:MUZIC:ALP2013-02-04T21:02:00Z<p>Adekunle Onipe: </p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in mammals. Protein members of this subfamily include: '''CLP36''' (also known as PDLIM1 or hCLIM1 (in human)<ref>PMID:10022510</ref> and Elfin (in mouse)<ref>PMID:11596114</ref>), '''Mystique''' (aka PDLIM2 or SLIM)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>, '''ALP''' (aka PDLIM3)<ref name="r1">PMID:9334352</ref> and '''RIL''' (aka PDLIM4).<br />
<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.<br />
<br />
hCLIM1/CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref> which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|400px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
<br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4 is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently known (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Structures ==<br />
Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu viral particle (the PDZ-binding motif), shows structural mechanism of binding with atomic specificity <ref name="e">doi:10.1371/journal.pone.0019511</ref>. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.<br />
<Structure load='2PKT' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human hCLIM1 in complex with the C-terminal peptide of α-actinin-1 (PDB code: 2PKT)[http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT]'/><br />
<Structure load='3PDV' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human PDLIM2 in complex with pathogenic bird flu viral peptide NS1 (PDB code: 3PDV)[http://www.pdb.org/pdb/explore/explore.do?structureId=3PDV]'/><br />
<Structure load='1X64' size='150' frame='true' align='right' caption='NMR solution structure of the LIM domain of mouse PDLIM3 (ALP) (PDB code: 1X64)[http://www.pdb.org/pdb/explore/explore.do?structureId=1X64]'/><br />
<Structure load='1v51' size='150' frame='true' align='right' caption='NMR solution structure of the PDZ domain of mouse PDLIM3 (ALP) (PDB code: 1v51)[http://www.rcsb.org/pdb/explore/explore.do?pdbId=1v5l]'/><br />
<Structure load='2V1W' size='150' frame='true' align='right' caption='X-ray crystal stucture of the PDZ domain of human PDLIM4 (RIL) in complex with human α-actinin-1C-terminal peptide (PDB code: 2V1W)[http://www.rcsb.org/pdb/explore/explore.do?structureId=2V1W]'/><br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin. Interestingly, a non-structural interacting partner as recently been identified; the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus (NS1) peptide<ref name="e">doi:10.1371/journal.pone.0019511</ref>. An elegant summary of other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M ''et al'' (2010) <ref name="c">doi:10.1093/jmcb/mjp038</ref> and te Velthius A.J. ''et al'' (2007) <ref name="d">DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
<br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been identified within the ALP subfamily<ref name="d">DOI 10.1100/tsw.2007.232</ref>, <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Human PDLIM2 (mystique) selectively interacts with highly pathogenic bird flu virus strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic viral protein to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the bird flu virus.<br />
<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1715568Group:MUZIC:ALP2013-02-04T20:55:56Z<p>Adekunle Onipe: </p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in mammals. Protein members of this subfamily include: '''CLP36''' (also known as PDLIM1 or hCLIM1 (in human)<ref>PMID:10022510</ref> and Elfin (in mouse)<ref>PMID:11596114</ref>), '''Mystique''' (aka PDLIM2 or SLIM)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>, '''ALP''' (aka PDLIM3)<ref name="r1">PMID:9334352</ref> and '''RIL''' (aka PDLIM4).<br />
<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.<br />
<br />
hCLIM1/CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref> which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|400px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
<br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4 is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently known (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Structures ==<br />
Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu viral particle (the PDZ-binding motif), shows structural mechanism of binding with atomic specificity <ref name="e">doi:10.1371/journal.pone.0019511</ref>. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.<br />
<Structure load='2PKT' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human hCLIM1 in complex with the C-terminal peptide of α-actinin-1 (PDB code: 2PKT)[http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT]'/><br />
<Structure load='3PDV' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human PDLIM2 in complex with pathogenic bird flu viral peptide NS1 (PDB code: 3PDV)[http://www.pdb.org/pdb/explore/explore.do?structureId=3PDV]'/><br />
<Structure load='1X64' size='150' frame='true' align='right' caption='NMR solution structure of the LIM domain of mouse PDLIM3(ALP)(PDB code: 1X64)[http://www.pdb.org/pdb/explore/explore.do?structureId=1X64]'/><br />
<Structure load='1v51' size='150' frame='true' align='right' caption='NMR solution structure of the PDZ domain of mouse PDLIM3(ALP)(PDB code: 1v51)[http://www.rcsb.org/pdb/explore/explore.do?pdbId=1v5l]'/><br />
<Structure load='2V1W' size='150' frame='true' align='right' caption='X-ray crystal stucture of the PDZ domain of human PDLIM4 (RIL) in complex with human α-actinin-1(PDB code: 2V1W)[http://www.rcsb.org/pdb/explore/explore.do?structureId=2V1W]'/><br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin. Interestingly, a non-structural interacting partner as recently been identified <ref name="e">doi:10.1371/journal.pone.0019511</ref>, where the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus (NS1) C-terminal peptide. An elegant summary of many other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M ''et al'' (2010) <ref name="c">doi:10.1093/jmcb/mjp038</ref> and te Velthius A.J. ''et al'' (2007) <ref name="d">DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
<br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been identified within the ALP subfamily<ref name="d">DOI 10.1100/tsw.2007.232</ref>, <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Human PDLIM2 (mystique) selectively interacts with highly pathogenic bird flu virus strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic viral protein to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the pathogenic bird flu virus.<br />
<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1715567Group:MUZIC:ALP2013-02-04T20:51:09Z<p>Adekunle Onipe: /* Structures */</p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in mammals. Protein members of this subfamily include: '''CLP36''' (also known as PDLIM1 or hCLIM1 (in human)<ref>PMID:10022510</ref> and Elfin (in mouse)<ref>PMID:11596114</ref>), '''Mystique''' (aka PDLIM2 or SLIM)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>, '''ALP''' (aka PDLIM3)<ref name="r1">PMID:9334352</ref> and '''RIL''' (aka PDLIM4).<br />
<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.<br />
<br />
hCLIM1/CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref> which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|400px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
<br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4, is the smallest at ~35.4 kDa of the ALP subfamily. Initially characterized in rat, it is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently identified (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Structures ==<br />
Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu viral particle (the PDZ-binding motif), shows structural mechanism of binding with atomic specificity <ref name="e">doi:10.1371/journal.pone.0019511</ref>. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.<br />
<Structure load='2PKT' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human hCLIM1 in complex with the C-terminal peptide of α-actinin-1 (PDB code: 2PKT)[http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT]'/><br />
<Structure load='3PDV' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human PDLIM2 in complex with pathogenic bird flu viral peptide NS1 (PDB code: 3PDV)[http://www.pdb.org/pdb/explore/explore.do?structureId=3PDV]'/><br />
<Structure load='1X64' size='150' frame='true' align='right' caption='NMR solution structure of the LIM domain of mouse PDLIM3(ALP)(PDB code: 1X64)[http://www.pdb.org/pdb/explore/explore.do?structureId=1X64]'/><br />
<Structure load='1v51' size='150' frame='true' align='right' caption='NMR solution structure of the PDZ domain of mouse PDLIM3(ALP)(PDB code: 1v51)[http://www.rcsb.org/pdb/explore/explore.do?pdbId=1v5l]'/><br />
<Structure load='2V1W' size='150' frame='true' align='right' caption='X-ray crystal stucture of the PDZ domain of human PDLIM4 (RIL) in complex with human α-actinin-1(PDB code: 2V1W)[http://www.rcsb.org/pdb/explore/explore.do?structureId=2V1W]'/><br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin-2 at the Z-disk. Interestingly, an interacting partner outside muscle Z-disk as recently been identified <ref name="e">doi:10.1371/journal.pone.0019511</ref>, where the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus NS1 C-terminal peptide. An elegant summary of many other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M ''et al'' (2010) <ref name="c">doi:10.1093/jmcb/mjp038</ref> and te Velthius A.J. ''et al'' (2007) <ref name="d">DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
<br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been identified within the ALP subfamily<ref name="d">DOI 10.1100/tsw.2007.232</ref>, <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Human PDLIM2 (mysitique) selectively interacts with highly pathogenic bird flu virus strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic viral protein to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the pathogenic bird flu virus.<br />
<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1715507Group:MUZIC:ALP2013-02-04T09:42:15Z<p>Adekunle Onipe: </p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in mammals. Protein members of this subfamily include: '''CLP36''' (also known as PDLIM1 or hCLIM1 (in human)<ref>PMID:10022510</ref> and Elfin (in mouse)<ref>PMID:11596114</ref>), '''Mystique''' (aka PDLIM2 or SLIM)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>, '''ALP''' (aka PDLIM3)<ref name="r1">PMID:9334352</ref> and '''RIL''' (aka PDLIM4).<br />
<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.<br />
<br />
hCLIM1/CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref> which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|400px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
<br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4, is the smallest at ~35.4 kDa of the ALP subfamily. Initially characterized in rat, it is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently identified (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Structures ==<br />
Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu virus PDZ-binding motif, shows structural mechanism of binding with atomic specificity <ref name="e">doi:10.1371/journal.pone.0019511</ref>. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.<br />
<Structure load='2PKT' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human hCLIM1 (PDB code: 2PKT)[http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT]'/><br />
<Structure load='3PDV' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human PDLIM2 in complex with pathogenic bird flu virus (PDB code: 3PDV)[http://www.pdb.org/pdb/explore/explore.do?structureId=3PDV]'/><br />
<Structure load='1X64' size='150' frame='true' align='right' caption='NMR solution structure of the LIM domain of mouse PDLIM3(ALP)(PDB code: 1X64)[http://www.pdb.org/pdb/explore/explore.do?structureId=1X64]'/><br />
<Structure load='1v51' size='150' frame='true' align='right' caption='NMR solution structure of the PDZ domain of mouse PDLIM3(ALP)(PDB code: 1v51)[http://www.rcsb.org/pdb/explore/explore.do?pdbId=1v5l]'/><br />
<Structure load='2V1W' size='150' frame='true' align='right' caption='X-ray crystal stucture of the PDZ domain of human PDLIM4 (RIL) in complex with human α-actinin-1(PDB code: 2V1W)[http://www.rcsb.org/pdb/explore/explore.do?structureId=2V1W]'/><br />
<br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin-2 at the Z-disk. Interestingly, an interacting partner outside muscle Z-disk as recently been identified <ref name="e">doi:10.1371/journal.pone.0019511</ref>, where the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus NS1 C-terminal peptide. An elegant summary of many other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M ''et al'' (2010) <ref name="c">doi:10.1093/jmcb/mjp038</ref> and te Velthius A.J. ''et al'' (2007) <ref name="d">DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
<br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been identified within the ALP subfamily<ref name="d">DOI 10.1100/tsw.2007.232</ref>, <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Human PDLIM2 (mysitique) selectively interacts with highly pathogenic bird flu virus strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic viral protein to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the pathogenic bird flu virus.<br />
<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1715487Group:MUZIC:ALP2013-02-03T13:42:53Z<p>Adekunle Onipe: </p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in mammals. Protein members of this subfamily include: '''CLP36''' (also known as PDLIM1 or hCLIM1 (in human)<ref>PMID:10022510</ref> and Elfin (in mouse)<ref>PMID:11596114</ref>), '''Mystique''' (aka PDLIM2 or SLIM)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>, '''ALP''' (aka PDLIM3)<ref name="r1">PMID:9334352</ref> and '''RIL''' (aka PDLIM4).<br />
<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.<br />
<br />
hCLIM1/CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref> which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|400px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
<br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4, is the smallest at ~35.4 kDa of the ALP subfamily. Initially characterized in rat, it is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently identified (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
<br />
<br />
== Structures ==<br />
Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu virus PDZ-binding motif, shows structural mechanism of binding with atomic specificity <ref name="e">doi:10.1371/journal.pone.0019511</ref>. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.<br />
<Structure load='2PKT' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human hCLIM1 (PDB code: 2PKT)[http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT]'/><br />
<Structure load='3PDV' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human PDLIM2 in complex with pathogenic bird flu virus (PDB code: 3PDV)[http://www.pdb.org/pdb/explore/explore.do?structureId=3PDV]'/><br />
<Structure load='1X64' size='150' frame='true' align='right' caption='NMR solution structure of the LIM domain of mouse PDLIM3(ALP)(PDB code: 1X64)[http://www.pdb.org/pdb/explore/explore.do?structureId=1X64]'/><br />
<Structure load='1v51' size='150' frame='true' align='right' caption='NMR solution structure of the PDZ domain of mouse PDLIM3(ALP)(PDB code: 1v51)[http://www.rcsb.org/pdb/explore/explore.do?pdbId=1v5l]'/><br />
<Structure load='2V1W' size='150' frame='true' align='right' caption='X-ray crystal stucture of the PDZ domain of human PDLIM4 (RIL) in complex with human α-actinin-1(PDB code: 2V1W)[http://www.rcsb.org/pdb/explore/explore.do?structureId=2V1W]'/><br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin-2 at the Z-disk. Interestingly, an interacting partner outside muscle Z-disk as recently been identified <ref name="e">doi:10.1371/journal.pone.0019511</ref>, where the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus NS1 C-terminal peptide. An elegant summary of many other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M ''et al'' (2010) <ref name="c">doi:10.1093/jmcb/mjp038</ref> and te Velthius A.J. ''et al'' (2007) <ref name="d">DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
<br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been identified within the ALP subfamily<ref name="d">DOI 10.1100/tsw.2007.232</ref>, <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Human PDLIM2 (mysitique) selectively interacts with highly pathogenic bird flu virus strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic viral protein to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the pathogenic bird flu virus.<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1715486Group:MUZIC:ALP2013-02-03T13:39:39Z<p>Adekunle Onipe: /* Structures */</p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in mammals. Protein members of this subfamily include: '''CLP36''' (also known as PDLIM1 or hCLIM1 (in human)<ref>PMID:10022510</ref> and Elfin (in mouse)<ref>PMID:11596114</ref>), '''Mystique''' (aka PDLIM2 or SLIM)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>, '''ALP''' (aka PDLIM3)<ref name="r1">PMID:9334352</ref> and '''RIL''' (aka PDLIM4).<br />
<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.<br />
<br />
hCLIM1/CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref> which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|400px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
<br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4, is the smallest at ~35.4 kDa of the ALP subfamily. Initially characterized in rat, it is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently identified (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
<br />
<br />
== Structures ==<br />
Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu virus PDZ-binding motif, shows structural mechanism of binding with atomic specificity <ref name="e">doi:10.1371/journal.pone.0019511</ref>. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.<br />
<Structure load='2PKT' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human hCLIM1 (PDB code: 2PKT)[http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT]'/><br />
<Structure load='3PDV' size='150' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human PDLIM2 in complex with pathogenic bird flu virus (PDB code: 3PDV)[http://www.pdb.org/pdb/explore/explore.do?structureId=3PDV]'/><br />
<Structure load='1X64' size='150' frame='true' align='right' caption='NMR solution structure of the LIM domain of mouse PDLIM3(ALP)(PDB code: 1X64)[http://www.pdb.org/pdb/explore/explore.do?structureId=1X64]'/><br />
<Structure load='1v51' size='150' frame='true' align='right' caption='NMR solution structure of the PDZ domain of mouse PDLIM3(ALP)(PDB code: 1v51)[http://www.rcsb.org/pdb/explore/explore.do?pdbId=1v5l]'/><br />
<Structure load='2V1W' size='150' frame='true' align='right' caption='X-ray crystal stucture of the PDZ domain of human PDLIM4 (RIL) in complex with human α-actinin-1(PDB code: 2V1W)[http://www.rcsb.org/pdb/explore/explore.do?structureId=2V1W]'/><br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin-2 at the Z-disk. Interestingly, an interacting partner outside muscle Z-disk as recently been identified <ref name="e">doi:10.1371/journal.pone.0019511</ref>, where the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus NS1 C-terminal peptide. An elegant summary of many other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M ''et al'' (2010) <ref name="c">doi:10.1093/jmcb/mjp038</ref> and te Velthius A.J. ''et al'' (2007) <ref name="d">DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been identified within the ALP subfamily<ref name="d">DOI 10.1100/tsw.2007.232</ref>, <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Human PDLIM2 (mysitique) selectively interacts with highly pathogenic bird flu virus strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic viral protein to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the pathogenic bird flu virus.<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1715481Group:MUZIC:ZASP2013-02-03T13:06:43Z<p>Adekunle Onipe: </p>
<hr />
<div>== Introduction==<br />
'''ZASP''' ('''Z'''-disc '''A'''lternatively '''S'''pliced '''P'''DZ-domain containing) protein, also referred to as LIM domain-binding protein 3 (LDB-3), is a 78 kDa, 727-amino-acid human ortholog of cypher (in mouse), independently located to striated heart and skeletal muscle cells<ref>PMID:10427098</ref>, as well as integrin adhesion sites in insect tissues <ref name="dp">doi: 10.1083/jcb.200707045</ref>. ZASP is a major component protein of striated muscle Z-disc and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has recently been characterised to bind α-actinin-2 and a very C-terminal class III motif in [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin] <ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers complementary interacting capabilities to ZASP, like the ability to interact with the spectrin repeats of α-actinin-2<ref>doi:10.1016/j.yexcr.2005.12.036</ref>. Together, these suggest ZASP plays an important role during myofibrillogenesis and the assembly of multi-protein complexes in muscle Z-discs as well as integrin adhesion sites <ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
<br />
[[Image:zasp-new.png|left|400px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
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<br />
==Structure==<br />
The solution structure of ZASP PDZ domain<ref>PMID:15062084</ref> revealed canonical PDZ domain fold containing six β-strands and 2 α-helices in a circular permutation mode common to PDZ domains. There is presently no known structure of the LIM domains of ZASP, neither is there an experimental structure for the ZASP PDZ domain fused with one or two of its binding partners. <Structure load='1rgw' size='200' frame='true' align='right' caption= 'NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: 1RGW) [http://www.rcsb.org/pdb/explore/explore.do?structureId=1RGW]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3'/><br />
<br />
==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the '''oracle''' of Z-disk multi-protein complexes by tethering and regulating interacting proteins via its PDZ and LIM domains. This is suggested by experimental evidences which show the PDZ domain of ZASP interacts with myotilin, FATZ protein family and α-actinin-2. Based on interaction with the class I PDZ-binding motif (PBM) of α-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. Recent report on interaction of ZASP PDZ domain with class III PBMs in myotilin and myozenin suggests that ZASP PDZ domain has dual capacity (or classification) and possible structural plasticity as it is able to bind both class I and class III motifs <ref name="b" /> from three different proteins. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
<br />
==Pathology==<br />
Muscle disorders resulting from aberration(s) in ZASP gene are described as ZASPopathies <ref>doi: 10.1093/brain/awm006</ref>.<br />
Mutations in the ZASP gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular non-compaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. ZASP as also been shown to be the major Z-disc component to have O-linked-β-N-acetylglucosamine; (O-GlcNAc) modification, with significant modification in diseased states <ref>PMID: 23271734</ref>; this possibly presents ZASP as a prominent marker of cardiac dysfunctionality and of diagnostic value. Recently, mutations in ZASP have been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganised and<br />
fragmented Z-lines in skeletal and cardiac muscle <ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1715478Group:MUZIC:Myotilin2013-02-03T12:52:15Z<p>Adekunle Onipe: /* Structure */</p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with a size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin (Ig)-like domains and a short C-terminal tail containing PDZ-binding motif (PBM).<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin(Ig)-like domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold <ref>PMID: 19466753</ref>.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
<br />
== Function and Interactions ==<br />
<br />
Myotilin participates in a network of multi-protein interactions within the sarcomere, mainly via its Ig-domains and both N/C-terminals. All myotilin binding partners are components of [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Interactome Z-disk] and include '''actin''' (binds via its Ig-domains),<ref>PMID:16122733</ref> '''α-actinin-2''' (binds via its N-terminal half),<ref name="a" /> '''filamin C''' (binds via the Ig-domains) <ref name="e">PMID: 11038172</ref>, '''FATZ-1''' (via the Ig-domains)<ref name="c">PMID: 16076904</ref> and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:ZASP '''ZASP'''] (binds via its C-terminal class III PDZ-binding motif)<ref name="d">PMID:19047374</ref>; as well as the muscle quality control proteins localised to the Z-discs ('''MuRF3 and MuRF1''')<ref>PMID: 16337382</ref>. Myotilin forms homodimer and efficiently cross-link and bundle actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle.<br />
The appearance of myotilin with α-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Up-regulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
<br />
== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathies <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutations, mostly in the N-terminal serine-rich part of the protein, cause the onset of most disorders <ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
<br />
== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1715477Group:MUZIC:Myotilin2013-02-03T12:51:37Z<p>Adekunle Onipe: /* Introduction */</p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with a size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin (Ig)-like domains and a short C-terminal tail containing PDZ-binding motif (PBM).<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin-like (Ig) domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold <ref>PMID: 19466753</ref>.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
<br />
<br />
<br />
== Function and Interactions ==<br />
<br />
Myotilin participates in a network of multi-protein interactions within the sarcomere, mainly via its Ig-domains and both N/C-terminals. All myotilin binding partners are components of [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Interactome Z-disk] and include '''actin''' (binds via its Ig-domains),<ref>PMID:16122733</ref> '''α-actinin-2''' (binds via its N-terminal half),<ref name="a" /> '''filamin C''' (binds via the Ig-domains) <ref name="e">PMID: 11038172</ref>, '''FATZ-1''' (via the Ig-domains)<ref name="c">PMID: 16076904</ref> and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:ZASP '''ZASP'''] (binds via its C-terminal class III PDZ-binding motif)<ref name="d">PMID:19047374</ref>; as well as the muscle quality control proteins localised to the Z-discs ('''MuRF3 and MuRF1''')<ref>PMID: 16337382</ref>. Myotilin forms homodimer and efficiently cross-link and bundle actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle.<br />
The appearance of myotilin with α-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Up-regulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
<br />
== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathies <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutations, mostly in the N-terminal serine-rich part of the protein, cause the onset of most disorders <ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
<br />
== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1715476Group:MUZIC:ZASP2013-02-03T12:44:45Z<p>Adekunle Onipe: </p>
<hr />
<div>== Introduction==<br />
'''ZASP''' ('''Z'''-disc '''A'''lternatively '''S'''pliced '''P'''DZ-domain containing) protein, also referred to as LIM domain-binding protein 3 (LDB-3), is a 78 kDa, 727-amino-acid human ortholog of cypher (in mouse), independently located to striated heart and skeletal muscle cells<ref>PMID:10427098</ref>, as well as integrin adhesion sites in insect tissues <ref name="dp">doi: 10.1083/jcb.200707045</ref>. ZASP is a major component protein of striated muscle Z-disc and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has recently been characterised to bind α-actinin-2 and a very C-terminal class III motif in [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin] <ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers complementary interacting capabilities to ZASP, like the ability to interact with the spectrin repeats of α-actinin-2<ref>doi:10.1016/j.yexcr.2005.12.036</ref>. Together, these suggest ZASP plays an important role during myofibrillogenesis and the assembly of multi-protein complexes in muscle Z-discs as well as integrin adhesion sites <ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
<br />
[[Image:zasp-new.png|left|400px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==Structure==<br />
The solution structure of ZASP PDZ domain<ref>PMID:15062084</ref> revealed canonical PDZ domain fold containing six β-strands and 2 α-helices in a circular permutation mode common to PDZ domains. There is presently no known structure of the LIM domains of ZASP, neither is there an experimental structure for the ZASP PDZ domain fused with one or two of its binding partners. <Structure load='1rgw' size='200' frame='true' align='right' caption= 'NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: 1RGW) [http://www.rcsb.org/pdb/explore/explore.do?structureId=1RGW]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3'/><br />
<br />
==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the '''oracle''' of Z-disk multi-protein complexes by tethering and regulating interacting proteins via its PDZ and LIM domains. This is suggested by experimental evidences which show the PDZ domain of ZASP interacts with myotilin, FATZ protein family and α-actinin-2. Based on interaction with the class I PDZ-binding motif (PBM) of α-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. Recent report on interaction of ZASP PDZ domain with class III PBMs in myotilin and myozenin suggests that ZASP PDZ domain has dual capacity (or classification) and possible structural plasticity as it is able to bind both class I and class III motifs <ref name="b" /> from three different proteins. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
<br />
==Pathology==<br />
Mutations in the ZASP gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular non-compaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. ZASP as also been shown to be the major Z-disc component to have O-linked-β-N-acetylglucosamine; (O-GlcNAc) modification, with significant modification in diseased states <ref>PMID: 23271734</ref>; this possibly presents ZASP as a prominent marker of cardiac dysfunctionality and of diagnostic value. Recently, mutations in ZASP have been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganised and<br />
fragmented Z-lines in skeletal and cardiac muscle <ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1715475Group:MUZIC:ZASP2013-02-03T12:39:53Z<p>Adekunle Onipe: </p>
<hr />
<div>== Introduction==<br />
'''ZASP''' ('''Z'''-disc '''A'''lternatively '''S'''pliced '''P'''DZ-domain containing) protein, also referred to as LIM domain-binding protein 3 (LDB-3), is a 78 kDa, 727-amino-acid human ortholog of cypher (in mouse), independently located to striated heart and skeletal muscle cells<ref>PMID:10427098</ref>, as well as integrin adhesion sites in insect tissues <ref name="dp">doi: 10.1083/jcb.200707045</ref>. ZASP is a major component protein of striated muscle Z-disc and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has recently been characterised to bind α-actinin-2 and a very C-terminal class III motif in [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin] <ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers complementary interacting capabilities to ZASP, like the ability to interact with the spectrin repeats of α-actinin-2<ref>doi:10.1016/j.yexcr.2005.12.036</ref>. Together, these suggest ZASP plays an important role during myofibrillogenesis and the assembly of multi-protein complexes in muscle Z-discs as well as integrin adhesion sites <ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
<br />
[[Image:zasp-new.png|left|500px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==Structure==<br />
The solution structure of ZASP PDZ domain<ref>PMID:15062084</ref> revealed canonical PDZ domain fold containing six β-strands and 2 α-helices in a circular permutation mode common to PDZ domains. There is presently no known structure of the LIM domains of ZASP, neither is there an experimental structure for the ZASP PDZ domain fused with one or two of its binding partners. <Structure load='1rgw' size='200' frame='true' align='center' caption= 'NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: 1RGW) [http://www.rcsb.org/pdb/explore/explore.do?structureId=1RGW]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3'/><br />
<br />
<br />
==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the '''oracle''' of Z-disk multi-protein complexes by tethering and regulating interacting proteins via its PDZ and LIM domains. This is suggested by experimental evidences which show the PDZ domain of ZASP interacts with myotilin, FATZ protein family and α-actinin-2. Based on interaction with the class I PDZ-binding motif (PBM) of α-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. Recent report on interaction of ZASP PDZ domain with class III PBMs in myotilin and myozenin suggests that ZASP PDZ domain has dual capacity (or classification) and possible structural plasticity as it is able to bind both class I and class III motifs <ref name="b" /> from three different proteins. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
<br />
==Pathology==<br />
Mutations in the ZASP gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular non-compaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. ZASP as also been shown to be the major Z-disc component to have O-linked-β-N-acetylglucosamine; (O-GlcNAc) modification, with significant modification in diseased states <ref>PMID: 23271734</ref>; this possibly presents ZASP as a prominent marker of cardiac dysfunctionality and of diagnostic value. Recently, mutations in ZASP have been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganised and<br />
fragmented Z-lines in skeletal and cardiac muscle <ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1715474Group:MUZIC:ZASP2013-02-03T12:18:59Z<p>Adekunle Onipe: /* Introduction */</p>
<hr />
<div>== Introduction==<br />
'''ZASP''' ('''Z'''-disc '''A'''lternatively '''S'''pliced '''P'''DZ-domain containing) protein, also referred to as LIM domain-binding protein 3 (LDB-3), is a 78 kDa, 727-amino-acid human ortholog of cypher (in mouse), independently located to striated heart and skeletal muscle cells<ref>PMID:10427098</ref>, as well as integrin adhesion sites in insect tissues <ref name="dp">doi: 10.1083/jcb.200707045</ref>. ZASP is a major component protein of striated muscle Z-disc and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has recently been characterised to bind α-actinin-2 and a very C-terminal class III motif in [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin] <ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers complementary interacting capabilities to ZASP, like the ability to interact with the spectrin repeats of α-actinin-2<ref>doi:10.1016/j.yexcr.2005.12.036</ref>. Together, these suggest ZASP plays an important role during myofibrillogenesis and the assembly of multi-protein complexes in muscle Z-discs as well as integrin adhesion sites <ref name="dp">doi: 10.1083/jcb.200707045</ref>.<br />
<br />
==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
<br />
[[Image:zasp-new.png|left|500px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==Structure==<br />
<Structure load='1rgw' size='200' frame='true' align='left' caption='NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: 1RGW)[http://www.rcsb.org/pdb/explore/explore.do?structureId=1RGW]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3'/>The solution structure of ZASP PDZ domain<ref>PMID:15062084</ref> revealed canonical PDZ domain fold containing six β-strands and 2 α-helices in a circular permutation mode common to PDZ domains. There is presently no known structure of the LIM domains of ZASP, neither is there an experimental structure for the ZASP PDZ domain fused with one or two of its binding partners<br />
<br />
==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the ''oracle'' of Z-disk multi-protein complexes by tethering and regulating interacting proteins via its PDZ and LIM domains. This is suggested by experimental evidences which show the PDZ domain of ZASP interacts with myotilin, FATZ protein family and α-actinin-2. Based on interaction with the class I PDZ-binding motif (PBM) of α-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. Recent report on interaction of ZASP PDZ domain with class III PBMs in myotilin and myozenin suggests that ZASP PDZ domain has dual capacity (or classification) and possible structural plasticity as it is able to bind both class I and class III motifs <ref name="b" /> from three different proteins. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
<br />
==Pathology==<br />
Mutations in the '''ZASP''' gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular noncompaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. Recently, mutations in ZASP have been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganized and<br />
fragmented Z-lines in skeletal and cardiac muscle <ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>.<br />
<br />
<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1715470Group:MUZIC:ZASP2013-02-03T11:50:31Z<p>Adekunle Onipe: /* Structure */</p>
<hr />
<div>== Introduction==<br />
'''ZASP''' ('''Z'''-disk '''A'''lternately '''S'''pliced '''P'''DZ domain) protein, also referred to as LIM domain-binding protein 3 (LDB-3), is the 78 kDa, 727-amino-acid human ortholog of cypher, independently identified in heart and skeletal muscle <ref>PMID:10427098</ref>. ZASP is a component protein of the striated muscle Z-disk and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has recently been characterized to bind a very C-terminal class III motif in [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin] <ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>, suggesting it plays an important role during myofibrillogenesis.<br />
<br />
==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
<br />
[[Image:zasp-new.png|left|500px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==Structure==<br />
<Structure load='1rgw' size='200' frame='true' align='left' caption='NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: 1RGW)[http://www.rcsb.org/pdb/explore/explore.do?structureId=1RGW]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3'/>The solution structure of ZASP PDZ domain<ref>PMID:15062084</ref> revealed canonical PDZ domain fold containing six β-strands and 2 α-helices in a circular permutation mode common to PDZ domains. There is presently no known structure of the LIM domains of ZASP, neither is there an experimental structure for the ZASP PDZ domain fused with one or two of its binding partners<br />
<br />
==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the ''oracle'' of Z-disk multi-protein complexes by tethering and regulating interacting proteins via its PDZ and LIM domains. This is suggested by experimental evidences which show the PDZ domain of ZASP interacts with myotilin, FATZ protein family and α-actinin-2. Based on interaction with the class I PDZ-binding motif (PBM) of α-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. Recent report on interaction of ZASP PDZ domain with class III PBMs in myotilin and myozenin suggests that ZASP PDZ domain has dual capacity (or classification) and possible structural plasticity as it is able to bind both class I and class III motifs <ref name="b" /> from three different proteins. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
<br />
==Pathology==<br />
Mutations in the '''ZASP''' gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular noncompaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. Recently, mutations in ZASP have been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganized and<br />
fragmented Z-lines in skeletal and cardiac muscle <ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>.<br />
<br />
<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1715469Group:MUZIC:ZASP2013-02-03T11:48:41Z<p>Adekunle Onipe: /* Function and Interactions */</p>
<hr />
<div>== Introduction==<br />
'''ZASP''' ('''Z'''-disk '''A'''lternately '''S'''pliced '''P'''DZ domain) protein, also referred to as LIM domain-binding protein 3 (LDB-3), is the 78 kDa, 727-amino-acid human ortholog of cypher, independently identified in heart and skeletal muscle <ref>PMID:10427098</ref>. ZASP is a component protein of the striated muscle Z-disk and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has recently been characterized to bind a very C-terminal class III motif in [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin] <ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>, suggesting it plays an important role during myofibrillogenesis.<br />
<br />
==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
<br />
[[Image:zasp-new.png|left|500px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==Structure==<br />
The solution structure of ZASP PDZ domain<ref>PMID:15062084</ref> revealed canonical PDZ domain fold containing six β-strands and 2 α-helices in a circular permutation mode common to PDZ domains. There is presently no known structure of the LIM domains of ZASP, neither is there an experimental structure for the ZASP PDZ domain fused with one or two of its binding partners <Structure load='1rgw' size='200' frame='true' align='right' caption='NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: 1RGW)[http://www.rcsb.org/pdb/explore/explore.do?structureId=1RGW]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3' /><br />
<br />
==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the ''oracle'' of Z-disk multi-protein complexes by tethering and regulating interacting proteins via its PDZ and LIM domains. This is suggested by experimental evidences which show the PDZ domain of ZASP interacts with myotilin, FATZ protein family and α-actinin-2. Based on interaction with the class I PDZ-binding motif (PBM) of α-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. Recent report on interaction of ZASP PDZ domain with class III PBMs in myotilin and myozenin suggests that ZASP PDZ domain has dual capacity (or classification) and possible structural plasticity as it is able to bind both class I and class III motifs <ref name="b" /> from three different proteins. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
<br />
==Pathology==<br />
Mutations in the '''ZASP''' gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular noncompaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. Recently, mutations in ZASP have been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganized and<br />
fragmented Z-lines in skeletal and cardiac muscle <ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>.<br />
<br />
<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1715467Group:MUZIC:ZASP2013-02-03T11:41:20Z<p>Adekunle Onipe: /* Structure */</p>
<hr />
<div>== Introduction==<br />
'''ZASP''' ('''Z'''-disk '''A'''lternately '''S'''pliced '''P'''DZ domain) protein, also referred to as LIM domain-binding protein 3 (LDB-3), is the 78 kDa, 727-amino-acid human ortholog of cypher, independently identified in heart and skeletal muscle <ref>PMID:10427098</ref>. ZASP is a component protein of the striated muscle Z-disk and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has recently been characterized to bind a very C-terminal class III motif in [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin] <ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>, suggesting it plays an important role during myofibrillogenesis.<br />
<br />
==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
<br />
[[Image:zasp-new.png|left|500px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
==Structure==<br />
The solution structure of ZASP PDZ domain<ref>PMID:15062084</ref> revealed canonical PDZ domain fold containing six β-strands and 2 α-helices in a circular permutation mode common to PDZ domains. There is presently no known structure of the LIM domains of ZASP, neither is there an experimental structure for the ZASP PDZ domain fused with one or two of its binding partners <Structure load='1rgw' size='200' frame='true' align='right' caption='NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: 1RGW)[http://www.rcsb.org/pdb/explore/explore.do?structureId=1RGW]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3' /><br />
<br />
==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the '''''oracle''''' of Z-disk multi-protein complexes. This is suggested by experimental evidences which show the PDZ domain interacts with myotilin, FATZ protein family and α-actinin-2. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
<br />
==Pathology==<br />
Mutations in the '''ZASP''' gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular noncompaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. Recently, mutations in ZASP have been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganized and<br />
fragmented Z-lines in skeletal and cardiac muscle <ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>.<br />
<br />
<br />
<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1715463Group:MUZIC:ALP2013-02-03T11:32:11Z<p>Adekunle Onipe: /* Pathology */</p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in mammals. Protein members of this subfamily include: '''CLP36''' (also known as PDLIM1 or hCLIM1 (in human)<ref>PMID:10022510</ref> and Elfin (in mouse)<ref>PMID:11596114</ref>), '''Mystique''' (aka PDLIM2 or SLIM)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>, '''ALP''' (aka PDLIM3)<ref name="r1">PMID:9334352</ref> and '''RIL''' (aka PDLIM4).<br />
<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.<br />
<br />
hCLIM1/CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref> which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|400px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
<br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4, is the smallest at ~35.4 kDa of the ALP subfamily. Initially characterized in rat, it is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently identified (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
<br />
<br />
== Structures ==<br />
Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu virus PDZ-binding motif, shows structural mechanism of binding with atomic specificity <ref name="e">doi:10.1371/journal.pone.0019511</ref>. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.<br />
<Structure load='2PKT' size='200' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human hCLIM1 (PDB code: 2PKT)[http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT]'/><br />
<Structure load='3PDV' size='200' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human PDLIM2 in complex with pathogenic bird flu virus (PDB code: 3PDV)[http://www.pdb.org/pdb/explore/explore.do?structureId=3PDV]'/><br />
<Structure load='1X64' size='200' frame='true' align='right' caption='NMR solution structure of the LIM domain of mouse PDLIM3(ALP)(PDB code: 1X64)[http://www.pdb.org/pdb/explore/explore.do?structureId=1X64]'/><br />
<Structure load='1v51' size='200' frame='true' align='right' caption='NMR solution structure of the PDZ domain of mouse PDLIM3(ALP)(PDB code: 1v51)[http://www.rcsb.org/pdb/explore/explore.do?pdbId=1v5l]'/><br />
<Structure load='2V1W' size='200' frame='true' align='right' caption='X-ray crystal stucture of the PDZ domain of human PDLIM4 (RIL) in complex with human α-actinin-1(PDB code: 2V1W)[http://www.rcsb.org/pdb/explore/explore.do?structureId=2V1W]'/><br />
<br />
<br />
<br />
<br />
<br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin-2 at the Z-disk. Interestingly, an interacting partner outside muscle Z-disk as recently been identified <ref name="e">doi:10.1371/journal.pone.0019511</ref>, where the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus NS1 C-terminal peptide. An elegant summary of many other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M ''et al'' (2010) <ref name="c">doi:10.1093/jmcb/mjp038</ref> and te Velthius A.J. ''et al'' (2007) <ref name="d">DOI 10.1100/tsw.2007.232</ref>. <br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been identified within the ALP subfamily<ref name="d">DOI 10.1100/tsw.2007.232</ref>, <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Human PDLIM2 (mysitique) selectively interacts with highly pathogenic bird flu virus strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic viral protein to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the pathogenic bird flu virus.<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1715462Group:MUZIC:ALP2013-02-03T11:30:10Z<p>Adekunle Onipe: </p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ- and LIM-domain containing proteins localised to cardiac and skeletal muscles in mammals. Protein members of this subfamily include: '''CLP36''' (also known as PDLIM1 or hCLIM1 (in human)<ref>PMID:10022510</ref> and Elfin (in mouse)<ref>PMID:11596114</ref>), '''Mystique''' (aka PDLIM2 or SLIM)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>, '''ALP''' (aka PDLIM3)<ref name="r1">PMID:9334352</ref> and '''RIL''' (aka PDLIM4).<br />
<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess only one C-terminal LIM domain, whereas Enigma family members possess three C-terminal LIM domains.<br />
<br />
hCLIM1/CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref> which shares a high degree of homology with the first protein members of the subfamily, that is, CLP36 and RIL <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Mystique (PDLIM2) is the most recent member of the family to be identified and characterised.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|400px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
<br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is a 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
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'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with molecular weight around 37.5 kDa, and 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4, is the smallest at ~35.4 kDa of the ALP subfamily. Initially characterized in rat, it is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently identified (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
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'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of CLP36 found in mouse and rat. The first member of the ALP subfamily with molecular weight of 36 kDa and 329 amino-acid sequence. Splice isoform for this protein is unknown (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
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== Structures ==<br />
Molecular structures of the PDZ or LIM domains of protein members of this subfamily are known; both in their apo forms and where presented, in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions. In particular, the recent crystal structure of the PDZ domain of human mystique (PDLIM2) in complex with the highly pathogenic avian flu virus PDZ-binding motif, shows structural mechanism of binding with atomic specificity <ref name="e">doi:10.1371/journal.pone.0019511</ref>. The structures for PDZ and LIM domains from human ALP (PDLIM3) are presently unknown, however the solution structures of both the PDZ and LIM domains of ALP from mouse have been solved.<br />
<Structure load='2PKT' size='200' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human hCLIM1 (PDB code: 2PKT)[http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT]'/><br />
<Structure load='3PDV' size='200' frame='true' align='right' caption='X-ray crystal structure of the PDZ domain of human PDLIM2 in complex with pathogenic bird flu virus (PDB code: 3PDV)[http://www.pdb.org/pdb/explore/explore.do?structureId=3PDV]'/><br />
<Structure load='1X64' size='200' frame='true' align='right' caption='NMR solution structure of the LIM domain of mouse PDLIM3(ALP)(PDB code: 1X64)[http://www.pdb.org/pdb/explore/explore.do?structureId=1X64]'/><br />
<Structure load='1v51' size='200' frame='true' align='right' caption='NMR solution structure of the PDZ domain of mouse PDLIM3(ALP)(PDB code: 1v51)[http://www.rcsb.org/pdb/explore/explore.do?pdbId=1v5l]'/><br />
<Structure load='2V1W' size='200' frame='true' align='right' caption='X-ray crystal stucture of the PDZ domain of human PDLIM4 (RIL) in complex with human α-actinin-1(PDB code: 2V1W)[http://www.rcsb.org/pdb/explore/explore.do?structureId=2V1W]'/><br />
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==Function and Interactions==<br />
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All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin-2 at the Z-disk. Interestingly, an interacting partner outside muscle Z-disk as recently been identified <ref name="e">doi:10.1371/journal.pone.0019511</ref>, where the PDZ domain of mystique (human PDLIM2) selectively interacts with the highly pathogenic bird flu virus NS1 C-terminal peptide. An elegant summary of many other molecular interactions and plausible functions of member proteins of ALP subfamily is presented by Zheng M ''et al'' (2010) <ref name="c">doi:10.1093/jmcb/mjp038</ref> and te Velthius A.J. ''et al'' (2007) <ref name="d">DOI 10.1100/tsw.2007.232</ref>. <br />
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==Pathology==<br />
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Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been indentified within the ALP subfamily<ref name="d">DOI 10.1100/tsw.2007.232</ref>, <ref name="c">doi:10.1093/jmcb/mjp038</ref>. Human PDLIM2 (mysitique) selecteively interacts with highly pathogenic bird flu viral strain H5N1 via its PDZ domain, and as PDLIM2 is localised to the human cardiac muscle, this interaction speculatively tethers the pathogenic peptide to the heart thereby mediating cardiac dysfunction likely with lethal effects associated to the pathogenic bird flu virus.<br />
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==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1705065Group:MUZIC:ALP2013-01-12T21:33:13Z<p>Adekunle Onipe: </p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ/LIM domain proteins of the cytoskeleton. Protein members of this subfamily include: '''ALP''' (also known as PDLIM3)<ref name="r1">PMID:9334352</ref>, '''CLP36''' (also known as hCLIM1 (in human)<ref>PMID:10022510</ref>, Elfin (in mouse)<ref>PMID:11596114</ref>, or PDLIM1), '''RIL''' (or PDLIM4) and '''Mystique''' (or SLIM, PDLIM2)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>.<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess an N-terminal PDZ domain and only '''one''' C-terminal LIM domain. <br />
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CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref>, which shares a high degree of homology with the first protein members of the subfamily - CLP36 and RIL <ref>doi:10.1093/jmcb/mjp038</ref>. Mystique is the most recently identified and characterised member of the ALP subfamily.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|500px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
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Apart from the PDZ/LIM domains, ALP subfamily members possess a conserved 34-amino-acid motif called '''ALP-like motif''' <ref>DOI 10.1100/tsw.2007.232</ref><br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is the 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with ~37.5 kDa, 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4, is the smallest at ~35.4 kDa of the ALP subfamily. Initially characterized in rat, it is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently identified (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
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'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of rat CLP36, the first member of the ALP subfamily. At 36 kDa and 329 amino acids, splice isoform of this protein is yet unidentified (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
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== Structures ==<br />
Molecular structures of the PDZ and/or LIM domains of [http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT PDLIM1 (hCLIM1/CLP36)], [http://www.pdb.org/pdb/results/results.do?qrid=185C6F4B&tabtoshow=Current PDLIM2 (Mystique)], [http://www.pdb.org/pdb/results/results.do?qrid=EDAB5DC2&tabtoshow=Current PDLIM3 (ALP)] and [http://www.pdb.org/pdb/results/results.do?qrid=D3075EE4&tabtoshow=Current PDLIM4 (RIL)] have been solved, in their apo form, and in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions.<br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin-2 at the Z-disk; an elegant summary of the molecular interactions and plausible functions of '''ALP''', '''Mystique''', '''RIL''', and '''hCLIM1''' can be found in <ref>DOI 10.1100/tsw.2007.232</ref> and <ref>doi:10.1093/jmcb/mjp038</ref>.<br />
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==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been indentified within the ALP subfamily <ref>DOI 10.1100/tsw.2007.232</ref> and <ref>doi:10.1093/jmcb/mjp038</ref>.<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1705064Group:MUZIC:ALP2013-01-12T21:31:56Z<p>Adekunle Onipe: </p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ/LIM domain proteins of the cytoskeleton. Protein members of this subfamily include: '''ALP''' (also known as PDLIM3)<ref name="r1">PMID:9334352</ref>, '''CLP36''' (also known as hCLIM1 (in human)<ref>PMID:10022510</ref>, Elfin (in mouse)<ref>PMID:11596114</ref>, or PDLIM1), '''RIL''' (or PDLIM4) and '''Mystique''' (or SLIM, PDLIM2)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>.<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess an N-terminal PDZ domain and only '''one''' C-terminal LIM domain. <br />
<br />
CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first protein members to be characterised in this subfamily. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref>, which shares a high degree of homology with the first protein members of the subfamily - CLP36 and RIL <ref>doi:10.1093/jmcb/mjp038</ref>. Mystique is the most recently identified and characterised member of the ALP subfamily.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|500px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
Apart from the PDZ/LIM domains, ALP subfamily members possess a conserved 34-amino-acid motif called '''ALP-like motif''' <ref>DOI 10.1100/tsw.2007.232</ref><br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is the 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with ~37.5 kDa, 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4, is the smallest at ~35.4 kDa of the ALP subfamily. Initially characterized in rat, it is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently identified (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of rat CLP36, the first member of the ALP subfamily. At 36 kDa and 329 amino acids, splice isoform of this protein is yet unidentified (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
== Structures ==<br />
Molecular structures of the PDZ and/or LIM domains of [http://www.pdb.org/pdb/explore/explore.do?structureId=2PKT PDLIM1 (hCLIM1/CLP36)], [http://www.pdb.org/pdb/results/results.do?qrid=185C6F4B&tabtoshow=Current PDLIM2 (Mystique)], [http://www.pdb.org/pdb/results/results.do?qrid=EDAB5DC2&tabtoshow=Current PDLIM3 (ALP)] and [http://www.pdb.org/pdb/results/results.do?qrid=D3075EE4&tabtoshow=Current PDLIM4 (RIL)] have been solved, in thier apo form, and in complex with the C-terminal extension of their binding partners. These structures present insightful features highlighting their respective interactions and functions.<br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin-2 at the Z-disk; an elegant summary of the molecular interactions and plausible functions of '''ALP''', '''Mystique''', '''RIL''', and '''hCLIM1''' can be found in <ref>DOI 10.1100/tsw.2007.232</ref> and <ref>doi:10.1093/jmcb/mjp038</ref>.<br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been indentified within the ALP subfamily <ref>DOI 10.1100/tsw.2007.232</ref> and <ref>doi:10.1093/jmcb/mjp038</ref>.<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ZASP&diff=1705063Group:MUZIC:ZASP2013-01-12T20:39:44Z<p>Adekunle Onipe: </p>
<hr />
<div>== Introduction==<br />
'''ZASP''' ('''Z'''-disk '''A'''lternately '''S'''pliced '''P'''DZ domain) protein, also referred to as LIM domain-binding protein 3 (LDB-3), is the 78 kDa, 727-amino-acid human ortholog of cypher, independently identified in heart and skeletal muscle <ref>PMID:10427098</ref>. ZASP is a component protein of the striated muscle Z-disk and a member of the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family enigma family] of proteins. Like most enigma family members, it possess an N-terminal PDZ domain and three C-terminal LIM domains. The PDZ domain has recently been characterized to bind a very C-terminal class III motif in [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myotilin myotilin] and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin myozenin] <ref name="b">PMID:19047374</ref>. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>, suggesting it plays an important role during myofibrillogenesis.<br />
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==Sequence annotation==<br />
Six alternatively spliced isoforms have been identified in human (UniProtKB ID: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)].<br />
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[[Image:zasp-new.png|left|500px|thumb| Domain organization in the first, canonical isoform of human ZASP]]<br />
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==Structure==<br />
The NMR structure of ZASP PDZ domain<ref>PMID:15062084</ref>,revealed canonical PDZ domain fold containing six β-strands and 2 α-helices. Based on interaction with a class I motif in alpha-actinin-2, the PDZ domain of ZASP is categorised as a typical class I interaction module. Recent report on interaction of ZASP PDZ domain with class III motifs in myotilin and FATZ family suggests that ZASP PDZ domain has dual capacity (or classification) as it is able to bind both class I and class III motifs <ref name="b" />. <Structure load='1rgw' size='200' frame='true' align='right' caption='NMR solution structure of the PDZ domain of recombinantly purified human ZASP (PDB code: 1RGW)[http://www.rcsb.org/pdb/explore/explore.do?structureId=1RGW]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/3' /><br />
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==Function and Interactions==<br />
PDZ domains are known to target proteins to sites of complex formation, as such ZASP functions most probably as the '''''oracle''''' of Z-disk multi-protein complexes. This is suggested by experimental evidences which show the PDZ domain interacts with myotilin, FATZ protein family and α-actinin-2. Apart from the PDZ domain, ZASP's internal motif (the ZASP-like motif) confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. In addition, there is increasing evidence that ZASP also performs signaling functions; the LIM domains of cypher (the mouse orthologue of ZASP) binds and directs PKC to the Z-disk, with mutation affecting this interaction <ref>PMID:10391924</ref>.<br />
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==Pathology==<br />
Mutations in the '''ZASP''' gene have been associated with dilated cardiomyopathy (DCM) and DCM<br />
associated with isolated left ventricular noncompaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>.<br />
The presence of multiple mutations in the ZASP gene in patients<br />
with DCM and INLVM suggests that disruption of this gene is a common cause of left ventricular<br />
dysfunction and dilation. Recently, mutations in ZASP have been linked to a novel form of muscular<br />
dystrophy in humans<ref>PMID:15668942</ref>. Furthermore, ZASP ablation in mice was shown to be embryonic or perinatal lethal,<br />
most likely due to functional failure in multiple striated muscle types that displayed disorganized and<br />
fragmented Z-lines in skeletal and cardiac muscle <ref>doi: 10.1083/jcb.200107092 </ref><ref>DOI 10.1100/tsw.2007.232</ref>.<br />
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==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1705026Group:MUZIC:Myotilin2013-01-10T21:45:22Z<p>Adekunle Onipe: </p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with the size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin-like (Ig) domains and a short C-terminal tail containing PDZ-binding motif.<br />
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== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
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== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin-like (Ig) domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold <ref>PMID: 19466753</ref>.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
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== Function and Interactions ==<br />
<br />
Myotilin participates in a network of multi-protein interactions within the sarcomere, mainly via its Ig-domains and both N/C-terminals. All myotilin binding partners are components of [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Interactome Z-disk] and include '''actin''' (binds via its Ig-domains),<ref>PMID:16122733</ref> '''alpha-actinin-2''' (binds via its N-terminal half),<ref name="a" /> '''filamin C''' (binds via the Ig-domains) <ref name="e">PMID: 11038172</ref>, '''FATZ-1''' (via the Ig-domains)<ref name="c">PMID: 16076904</ref> and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:ZASP '''ZASP'''] (binds via its C-terminal class III PDZ-binding motif)<ref name="d">PMID:19047374</ref>; as well as the muscle quality control proteins localised to the Z-discs ('''MuRF3 and MuRF1''')<ref>PMID: 16337382</ref>. Myotilin forms homodimer and efficiently cross-link and bundle actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle.<br />
The appearance of myotilin with alpha-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Up-regulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
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== Pathology ==<br />
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Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathy <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutation, mostly in the N-terminal serine-rich part of the protein, causes the onset of most disorders. Thus, mutation has a dominant negative effect on the functionality of myotilin.<ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
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== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1705025Group:MUZIC:Myotilin2013-01-10T21:38:25Z<p>Adekunle Onipe: </p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with the size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin-like (Ig) domains and a short C-terminal tail containing PDZ-binding motif.<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
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<br />
== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin-like (Ig) domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold <ref>PMID: 19466753</ref>.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
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<br />
== Function and Interactions ==<br />
<br />
Myotilin participates in a network of [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Interactome multi-protein interactions within the sarcomere], mainly via its Ig-domains and both N/C-terminals. All myotilin binding partners are components of Z-disk and include '''actin''' (binds via its Ig-domains),<ref>PMID:16122733</ref> '''alpha-actinin-2''' (binds via its N-terminal half),<ref name="a" /> '''filamin C''' (binds via the Ig-domains) <ref name="e">PMID: 11038172</ref>, '''FATZ-1''' (via the Ig-domains)<ref name="c">PMID: 16076904</ref> and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:ZASP '''ZASP'''] (binds via its C-terminal class III PDZ-binding motif)<ref name="d">PMID:19047374</ref>; as well as the muscle quality control proteins localised to the Z-discs ('''MuRF3 and MuRF1''')<ref>PMID: 16337382</ref>. Myotilin forms homodimer and efficiently cross-link and bundle actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle.<br />
The appearance of myotilin with alpha-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Up-regulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
<br />
== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathy <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutation, mostly in the N-terminal serine-rich part of the protein, causes the onset of most disorders. Thus, mutation has a dominant negative effect on the functionality of myotilin.<ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
<br />
== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1705024Group:MUZIC:ALP2013-01-10T21:33:36Z<p>Adekunle Onipe: </p>
<hr />
<div>==Introduction==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ/LIM domain proteins of the cytoskeleton. Protein members of this subfamily include: '''ALP''' (also known as PDLIM3)<ref name="r1">PMID:9334352</ref>, '''CLP36''' (also known as hCLIM1 (in human)<ref>PMID:10022510</ref>, Elfin (in mouse)<ref>PMID:11596114</ref>, or PDLIM1), '''RIL''' (or PDLIM4) and '''Mystique''' (or SLIM, PDLIM2)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>.<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess an N-terminal PDZ domain and only '''one''' C-terminal LIM domain. <br />
<br />
CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first to be characterized. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref>, which shares a high degree of homology with previously characterized CLP36 and RIL proteins<ref>doi:10.1093/jmcb/mjp038</ref>. Mystique is the most recently identified and characterized member of this subfamily.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|500px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
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<br />
Apart from the PDZ/LIM domains, all ALP subfamily members possess a conserved 34-amino-acid motif called '''ALP-like motif''' <ref>DOI 10.1100/tsw.2007.232</ref><br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is the 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with ~37.5 kDa, 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4, is the smallest at ~35.4 kDa of the ALP subfamily. Initially characterized in rat, it is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently identified (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of rat CLP36, the first member of the ALP subfamily. At 36 kDa and 329 amino acids, splice isoform of this protein is yet unidentified (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
== Structures ==<br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin-2 at the Z-disk; an elegant summary of the molecular interactions and plausible functions of '''ALP''', '''Mystique''', '''RIL''', and '''hCLIM1''' can be found in <ref>DOI 10.1100/tsw.2007.232</ref> and <ref>doi:10.1093/jmcb/mjp038</ref>.<br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been indentified within the ALP subfamily <ref>DOI 10.1100/tsw.2007.232</ref> and <ref>doi:10.1093/jmcb/mjp038</ref>.<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:ALP&diff=1705023Group:MUZIC:ALP2013-01-10T21:29:44Z<p>Adekunle Onipe: </p>
<hr />
<div>==Introduction: ALP subfamily==<br />
The '''ALP subfamily''' (α-'''A'''ctinin-associated '''L'''IM domain '''P'''roteins) comprises four PDZ/LIM domain proteins of the cytoskeleton. Protein members of this subfamily include: '''ALP''' (also known as PDLIM3)<ref name="r1">PMID:9334352</ref>, '''CLP36''' (also known as hCLIM1 (in human)<ref>PMID:10022510</ref>, Elfin (in mouse)<ref>PMID:11596114</ref>, or PDLIM1), '''RIL''' (or PDLIM4) and '''Mystique''' (or SLIM, PDLIM2)<ref name=a>PMID:15505042</ref><ref name=b>PMID:15659642</ref>.<br />
On the basis of structural similarities, the ALP subfamily are related to the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily], possessing [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY PDZ] and [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=LIM&BLAST=DUMMY LIM] domains, as well as internal motifs ''viz'' ALP-like motif (AM) and ZASP-like motif (ZM). However, the ALP subfamily differs from the [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Enigma_Family Enigma subfamily] as each member of the ALP subfamily possess an N-terminal PDZ domain and only '''one''' C-terminal LIM domain. <br />
<br />
CLP36 ('''C'''-terminal '''L'''IM '''P'''rotein '''36''' kDa)<ref>PMID:8522188</ref> and RIL ('''R'''eversion-'''I'''nduced '''L'''IM)<ref>PMID:7824279</ref> were the first to be characterized. α-Actinin-associated LIM protein (ALP) was later identified as a 39 kDa protein in rat skeletal muscle with a slightly shorter isoform in heart <ref name="r1">PMID:9334352</ref>, which shares a high degree of homology with previously characterized CLP36 and RIL proteins<ref>doi:10.1093/jmcb/mjp038</ref>. Mystique is the most recently identified and characterized member of this subfamily.<br />
<br />
==Sequence annotation==<br />
[[Image:ALP-subfamily.png|left|500px|thumb| Domain map in the first isoforms of human ALP subfamily members: <br />
'''ALP''' [http://www.uniprot.org/uniprot/Q53GG5#section_features] '''Mystique''' [http://www.uniprot.org/uniprot/Q96JY6] '''RIL''' [http://www.uniprot.org/uniprot/P50479#section_features] '''hCLIM1'''[http://www.uniprot.org/uniprot/O00151#section_features]]]<br />
<br />
<br />
<br />
Apart from the PDZ/LIM domains, all ALP subfamily members possess a conserved 34-amino-acid motif called '''ALP-like motif''' <ref>DOI 10.1100/tsw.2007.232</ref><br />
<br />
'''ALP''' (PDLIM3: PDZ and LIM domain protein 3) is the 39 kDa, 364 amino-acid protein present in heart and skeletal<br />
muscle with three splice isoforms presently identified UniProtKB ID: Q53GG5 [http://www.uniprot.org/uniprot/Q53GG5#section_features]. Apart from the PDZ domain, ALP carries two internal motifs (ZASP-like motif) and (ALP-like motif) which confers the ability to interact with α-actinin-2. <br />
<br />
'''Mystique''', identified in human and also referred to as PDLIM2, is the most recent member of the family with ~37.5 kDa, 352 amino-acid<ref>PMID:10429367</ref>. Four alternatively spliced isoforms have been described (UniProtKB ID:Q96JY6)[http://www.uniprot.org/uniprot/Q96JY6].<br />
<br />
'''RIL''' protein, alternatively referred to as PDLIM4, is the smallest at ~35.4 kDa of the ALP subfamily. Initially characterized in rat, it is well conserved in diverse species with 330 amino acids. Two alternatively spliced isoforms are presently identified (UniProtKB ID: P50479)[http://www.uniprot.org/uniprot/P50479#section_features].<br />
<br />
'''hCLIM1''' also referred to as PDLIM1, is the human orthologue of rat CLP36, the first member of the ALP subfamily. At 36 kDa and 329 amino acids, splice isoform of this protein is yet unidentified (UniProtKB ID:O00151 [http://www.uniprot.org/uniprot/O00151#section_features].<br />
<br />
== Structures ==<br />
<br />
==Function and Interactions==<br />
<br />
All member proteins of ALP subfamily have been shown to interact with component proteins of the cytoskeleton, particularly α-actinin-2 at the Z-disk; an elegant summary of the molecular interactions and plausible functions of '''ALP''', '''Mystique''', '''RIL''', and '''hCLIM1''' can be found in <ref>DOI 10.1100/tsw.2007.232</ref> and <ref>doi:10.1093/jmcb/mjp038</ref>.<br />
<br />
==Pathology==<br />
<br />
Deficiency in cardiac development and cardiac malfunction resulting from mutation and genetic studies have been indentified within the ALP subfamily <ref>DOI 10.1100/tsw.2007.232</ref> and <ref>doi:10.1093/jmcb/mjp038</ref>.<br />
<br />
==References==<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1705022Group:MUZIC:Myotilin2013-01-10T21:07:15Z<p>Adekunle Onipe: </p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with the size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin-like (Ig) domains and a short C-terminal tail containing PDZ-binding motif.<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
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<br />
== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin-like (Ig) domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold <ref>PMID: 19466753</ref>.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
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<br />
<br />
<br />
== Function and Interaction ==<br />
<br />
Myotilin participates in a network of [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Interactome multi-protein interactions within the sarcomere], mainly via its Ig-domains and both N/C-terminals. All myotilin binding partners are components of Z-disk and include '''actin''' (binds via its Ig-domains),<ref>PMID:16122733</ref> '''alpha-actinin-2''' (binds via its N-terminal half),<ref name="a" /> '''filamin C''' (binds via the Ig-domains) <ref name="e">PMID: 11038172</ref>, '''FATZ-1''' (via the Ig-domains)<ref name="c">PMID: 16076904</ref> and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:ZASP '''ZASP'''] (binds via its C-terminal class III PDZ-binding motif)<ref name="d">PMID:19047374</ref>; as well as the muscle quality control proteins localised to the Z-discs ('''MuRF3 and MuRF1''')<ref>PMID: 16337382</ref>. Myotilin forms homodimer and efficiently cross-link and bundle actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle.<br />
The appearance of myotilin with alpha-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Up-regulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
<br />
== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathy <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutation, mostly in the N-terminal serine-rich part of the protein, causes the onset of most disorders. Thus, mutation has a dominant negative effect on the functionality of myotilin.<ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
<br />
== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1705021Group:MUZIC:Myotilin2013-01-10T21:03:59Z<p>Adekunle Onipe: </p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with the size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin-like (Ig) domains and a short C-terminal tail containing PDZ-binding motif.<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
<br />
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<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin-like (Ig) domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold <ref>PMID: 19466753</ref>.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
<br />
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<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Function and Interaction ==<br />
<br />
Myotilin participates in a network of [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Interactome:multi-protein interactions within the sarcomere], mainly via its Ig-domains and both N/C-terminals. All myotilin binding partners are components of Z-disk and include '''actin''' (binds via its Ig-domains),<ref>PMID:16122733</ref> '''α-actinin-2''' (binds via its N-terminal half),<ref name="a" /> '''filamin C''' (binds via the Ig-domains) <ref name="e">PMID: 11038172</ref>, '''FATZ-1''' (via the Ig-domains)<ref name="c">PMID: 16076904</ref> and [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:ZASP:'''ZASP'''] (binds via its C-terminal class III PDZ-binding motif)<ref name="d">PMID:19047374</ref>; as well as the muscle quality control proteins localised to the Z-discs ('''MuRF3 and MuRF1''')<ref>PMID: 16337382</ref>. Myotilin forms homodimer and efficiently cross-link and bundle actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle.<br />
The appearance of myotilin with alpha-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Up-regulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
<br />
== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathy <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutation, mostly in the N-terminal serine-rich part of the protein, causes the onset of most disorders. Thus, mutation has a dominant negative effect on the functionality of myotilin.<ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
<br />
== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1705020Group:MUZIC:Myotilin2013-01-10T20:51:35Z<p>Adekunle Onipe: </p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with the size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin-like (Ig) domains and a short C-terminal tail containing PDZ-binding motif.<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
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== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin-like (Ig) domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold <ref>PMID: 19466753</ref>.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
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== Function and Interaction ==<br />
<br />
Myotilin participates in a network of multi-protein interactions within the sarcomere, mainly via its Ig-domains and both N/C-terminals. All myotilin binding partners are components of Z-disk and include '''actin''' (binds via its Ig-domains),<ref>PMID:16122733</ref> '''α-actinin-2''' (binds via its N-terminal half),<ref name="a" /> '''filamin C''' (binds via the Ig-domains) <ref name="e">PMID: 11038172</ref>, '''FATZ-1''' (via the Ig-domains)<ref name="c">PMID: 16076904</ref> and '''ZASP''' (binds via its C-terminal class III PDZ-binding motif)<ref name="d">PMID:19047374</ref>; as well as the muscle quality control proteins localised to the Z-discs ('''MuRF3 and MuRF1''')<ref>PMID: 16337382</ref>. Myotilin forms homodimer and efficiently cross-link and bundle actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle.<br />
The appearance of myotilin with alpha-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Up-regulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
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== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathy <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutation, mostly in the N-terminal serine-rich part of the protein, causes the onset of most disorders. Thus, mutation has a dominant negative effect on the functionality of myotilin.<ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
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== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1705015Group:MUZIC:Myotilin2013-01-10T17:54:46Z<p>Adekunle Onipe: </p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with the size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin-like (Ig) domains and a short C-terminal tail containing PDZ-binding motif.<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
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<br />
== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin-like (Ig) domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
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<br />
== Function and Interaction ==<br />
<br />
Myotilin participates in a network of multi-protein interactions within the sarcomere, mainly via its Ig-domains and both N/C-terminals. All myotilin binding partners are components of Z-disk and include '''actin''' (binds via its Ig-domains),<ref>PMID:16122733</ref> '''α-actinin-2''' (binds via its N-terminal half),<ref name="a" /> '''filamin C''' (binds via the Ig-domains) <ref name="e">PMID: 11038172</ref>, '''FATZ''' (via the Ig-domains)<ref name="c">PMID: 16076904</ref> and '''ZASP''' (binds via its C-terminal class III PDZ-binding motif)<ref name="d">PMID:19047374</ref>; as well as the muscle quality control proteins localised to the Z-discs ('''MuRF3 and MuRF1''')<ref>PMID: 16337382</ref>. Myotilin forms homodimer and efficiently cross-link and bundle actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle.<br />
The appearance of myotilin with alpha-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Up-regulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
<br />
== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathy <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutation, mostly in the N-terminal serine-rich part of the protein, causes the onset of most disorders. Thus, mutation has a dominant negative effect on the functionality of myotilin.<ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
<br />
== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1704998Group:MUZIC:Myotilin2013-01-10T09:27:27Z<p>Adekunle Onipe: </p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with the size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin-like (Ig) domains and a short C-terminal tail containing PDZ-binding motif.<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
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== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin-like (Ig) domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
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== Function and Interaction ==<br />
<br />
All myotilin's binding partners are components of Z-disk and include actin,<ref>PMID:16122733</ref> α-actinin-2,<ref name="a" /> filamin C<ref name="e">PMID: 11038172</ref>, FATZ<ref name="c">PMID: 16076904</ref> and ZASP<ref name="d">PMID:19047374</ref>; as well as the muscle quality control proteins localised to the Z-discs (MuRF3 and MuRF1)<ref>PMID: 16337382</ref>. Myotilin forms homodimer and efficiently cross-link and bundle actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle.<br />
The appearance of myotilin with alpha-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Up-regulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair <ref> PMID: 17056257 </ref>. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
<br />
== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathy <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutation, mostly in the N-terminal serine-rich part of the protein, causes the onset of most disorders. Thus, mutation has a dominant negative effect on the functionality of myotilin.<ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
<br />
== References ==<br />
<br />
<references/></div>Adekunle Onipehttps://proteopedia.org/index.php?title=Group:MUZIC:Myotilin&diff=1704997Group:MUZIC:Myotilin2013-01-10T09:25:31Z<p>Adekunle Onipe: </p>
<hr />
<div>'''<br />
== Introduction ==<br />
'''<br />
<br />
Myotilin is a 498-amino-acid cytoskeletal protein with the size of 55 kDa, localized in sarcomeric Z-discs of both skeletal and cardiac muscle<ref name="a">PMID:10369880</ref>. It belongs to a small group of scaffolding proteins, together with palladin and myopapalladin, which regulate actin organisation<ref>PMID:16164966</ref>. Myotilin consists of a unique serine-rich N-terminus, followed by two C-terminal half immunoglobulin-like (Ig) domains and a short C-terminal tail containing PDZ-binding motif.<br />
<br />
== Sequence annotation ==<br />
Two alternately-spliced isoforms of human myotilin are currently known [http://www.uniprot.org/uniprot/Q9UBF9 (UNIPROT Myotilin)]. Isoform-1 with 498 amino-acid sequence is the canonical form, while the second isoform lacks the first 184 amino-acid sequence.<br />
[[Image:Myotilin-isoforms2.png|left|450px| Domain organisation in myotilin. Alternately spliced isoform-2 lacks the first 184 amino-acid residues]]<br />
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<br />
<br />
== Structure ==<br />
Molecular structures of individual myotilin immunoglobulin-like (Ig) domains have recently been solved. The first domain (Ig-1) exhibits an I-type Ig-fold <ref name="b"> PMID: 19418025</ref>, while the second domain (Ig-2) is of typical C2-type Ig-domain fold.<Structure load='2KDG' size='200' frame='true' align='right' caption='Solution NMR structure of the first Ig-domain of human myotilin (PDB ID: 2KDG [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kdg]' scene='User:Denisa_Mullerova/workbench/2kdg/1'/><br />
<Structure load='2KKQ' size='200' frame='true' align='right' caption='Solution NMR structure of the second Ig-like (C2-type) domain of human myotilin (PDB ID:2KKQ [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kkq]' scene='User:Denisa_Mullerova/workbench/2kkq/1'/><br />
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<br />
<br />
<br />
== Function and Interaction ==<br />
<br />
All myotilin's binding partners are components of Z-disk and include actin,<ref>PMID:16122733</ref> α-actinin-2,<ref name="a" /> filamin C<ref name="e">PMID: 11038172</ref>, FATZ<ref name="c">PMID: 16076904</ref> and ZASP<ref name="d">PMID:19047374</ref>; as well as the muscle quality control proteins localised to the Z-discs (MuRF3 and MuRF1)<ref>PMID: 16337382</ref>. Myotilin forms homodimer and efficiently cross-link and bundle actin filaments<ref name="a" />, suggesting a contributory function in maintenance of contractile straited muscle <ref> PMID: 17056257 </ref>. <br />
The appearance of myotilin with alpha-actinin-2 and other proteins in Z-bodies of premyofibrils, at the very early stage of myofibre development, suggests essential role for myotilin in muscle formation <ref>PMID: 20625425</ref> <ref>PMID: 22021208</ref>. Up-regulation of myotilin after exercise-induced alteration of myofibril and/or during myofibrillar remodelling (insertion of new sarcomeres into pre-exisitng myofibrils), suggests a role for myotilin essential in muscle repair. Muscle disorders such as limb-girdle muscular dystrophy type 1A (LGMD1A) and myofibrillar myopathy (MFM) often resulting from several point mutations in myotilin, have further linked the protein to stabilisation role in myofibrils <ref>PMID:17074808</ref>.<br />
<br />
== Pathology ==<br />
<br />
Muscle disorders resulting from aberration(s) in myotilin gene are described as myotilinopathy <ref> PMID: 15947064 </ref>, <ref> PMID: 16793270</ref>. The disorders typically manifest as progressive proximal weakness of the extremities, pseudo-hypertropthy <ref>PMID: 19027924</ref> and atrophy, but may also include cardiomyopathy and peripheral neuropathy. Ultrastructural changes include Z-disk alterations and accumulation of dense filamentous myotilin. Single missense mutation, mostly in the N-terminal serine-rich part of the protein, causes the onset of most disorders. Thus, mutation has a dominant negative effect on the functionality of myotilin.<ref>PMID:10958653</ref> <ref>PMID:19181098</ref><br />
<br />
== References ==<br />
<br />
<references/></div>Adekunle Onipe