2013-04-02T11:58:04Z

Nikos Pinotsis:

These proteins from the muscle Z-disk interactome are being studied and annotated by the MUZIC network.

* [[Group:MUZIC:actinin2|α-actinin-2]]
* [[Group:MUZIC:ALP|ALP]]
* [[Group:MUZIC:ANKRD2|ANKRD2]]
* [[Group:MUZIC:Calcineurin|Calcineurin]]
* [[Group:MUZIC:CARP|ANKRD1]] (Also known as CARP)
* [[Group:MUZIC:CapZ|CapZ]]
* [[Group:MUZIC:Enigma_Family|Enigma_Family]]
* [[Group:MUZIC:FilaminC|Filamin-C]]
* [[Group:MUZIC:Myostatin|GDF-8]] (Also known as Myostatin)
* [[Group:MUZIC:Mena_VASP|Mena/Ena/VASP]]
* [[Group:MUZIC:MLP|CSRP3]] (Also known as MLP)
* [[Group:MUZIC:Myopalladin|Myopalladin]]
* [[Group:MUZIC:Myotilin|Myotilin]]
* [[Group:MUZIC:Myozenin|Myozenin-1]] (Also known as Calsarcin, FATZ)
* [[Group:MUZIC:Nebulin|Nebulin]]
* [[Group:MUZIC:Obscurin|Obscurin]]
* [[Group:MUZIC:Plectin|Plectin]]
* [[Group:MUZIC:Synaptopodin|Synaptopodin]]
* [[Group:MUZIC:Myopodin|Synaptopodin-2]] (Also known as Myopodin)
* [[Group:MUZIC:Tritopodin|Synaptopodin 2-like]] (Also known as Tritopodin)
* [[Group:MUZIC:Telethonin|Telethonin]]
* [[Group:MUZIC:Titin|Titin]]
* [[Group:MUZIC:XIN|XIN]]
* [[Group:MUZIC:ZASP|ZASP]]
* [[Group:MUZIC:Zyxin|Zyxin]]

Group:MUZIC:Telethonin

2013-04-02T11:55:38Z

Nikos Pinotsis: /* Sequence Annotation */

= Telethonin =

Also known as T-Cap or Titin Cap protein.

== Introduction ==

Telethonin is a small protein composed of 167 amino acids with a molecular weight of 19KDa predominantly expressed in striated muscle. Located at the Z-disk, it is involved with the structural machinery of the sarcomere, linking titin and other proteins implicated in sarcomere structure and signalling pathways.

Telethonin is encoded by the ''TCAP'' in humans (''Homo sapiens''), located on the long arm of chromosome 17, and by ''Tcap'' gene in mice (''Mus musculus'') located on chromosome 11. No known homologues have been reported,''Tcap'' is encoded by two exons, and has non-conserved intragenic sequences. The gene is flanked by two other genes: ''Stard3'' upstream separated by 2,8kb, and ''Pnmt1'' downstream separated by 1,7kb. ''Tcap'' has three conserved E-box elements at -103bp (E1), -272bp (E2), and -2067bp (E3).
Transcriptional activation of ''Tcap'' depends predominantly on the regulation of E1, with MyoD playing an important role throughout development, and myogenin more important during late differentiation into myoblasts. <ref>PMID:21305318</ref>

[[Image:Tcap regulation2.jpg]]

''Tcap'' is one of the most abundant transcripts in skeletal muscle <ref>PMID:9350988</ref> and is expreessed at similar levels in fast and slow skeletal muscle, althought expression levels are lower in neonatal compared to adult striated muscle. The transcript accumulates in a linear pattern similar to that of the myosin heavy chain <ref name="Mason"> PMID:16678796 </ref>. Studies have reported that denervation leads to decrease expression of ''Tcap'', suggesting that locomotor activity is a potential regulator .

<StructureSection load='1ya5' size='300' frame='true' align='right' caption='Telethonin crystal structure in red by Zou et al. (2006) when it is interacting with Z1 (in blue) and Z2 (in cyan) Titin domains (PDB entry: [http://www.pdb.org/pdb/explore/explore.do?structureId=1ya5 1ya5])' scene='Group:MUZIC:Telethonin/Titin_teletonin/1'/>

== Sequence Annotation ==

Telethonin is formed of 167 amino acids, and exhibits high similarity among species. The sequences of [http://www.uniprot.org/uniprot/O15273 human], [http://www.uniprot.org/uniprot/O70548 mouse], [http://www.uniprot.org/uniprot/Q6T8D8 bovine], [http://www.uniprot.org/uniprot/A4GR69 porcine] telethonin are available from Uniprot.

== Structure ==

Accumulation of telethonin is restricted to skeletal and cardiac, and t is one of the major components of the sarcomere. While predominantly localized at the Z-disk, it has also been reported to be localized within the nucleus.<ref>PMID:12379311 </ref>, <ref name="a"> PMID:16678796 </ref>

Structural studies by Zou et al. <ref name="b"> PMID:16407954 </ref> <scene name='User:Marcia_Ivonne_Pena_Paz/workbench/Telethonin/Telethonin_nter_cter/1'> describe five stranded antiparallel β-sheets extended by two wing-shaped β-hairpin motifs (A-B, C-D). These two motifs are related by an approximate two-fold symmetry, which generates an almost perfect palindromic arrangement.</scene> (N-terminal in blue and C-ter in orange). This structure is only found in the presence of <scene name='Group:MUZIC:Telethonin/Titin_teletonin/1'>titin</scene>, Telethonin might adopt a different fold in its absence.

The structure of telethonin was determined using X-ray crystallography. <ref>PMID:12446666</ref>,<ref name="b" /> The shape and architecture of the complex of Titin/Telethonin was studied by small-angle- X-ray scattering (SAXS) and then compared to the crystallographic models. <ref>PMID:16713295</ref>

This symmetry of telethonin permits its interaction with titin. Both are assembled in an antiparallel
(titin:telethonin). Titin N-terminal domains Z1 and Z2 (two Ig like repeats) interact with the C-terminal region of telethonin (residues 1-53), whereas telethonin mediates the antiparallel assembly of the two Z1Z2 domains.

== Function and Interactions ==

In early differentiating myocytes [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Titin titin] C-terminal and telethonin co-localize, targeting titin kinase is close to C-terminal phosphorylation site of telethonin. This phosphorylation is involved in the reorganization of the cytoskeleton during myofibrillogenesis. <ref name="c"> PMID:9804419 </ref> This particular co-localization is not seen in adult myofibrils, and titin kinase is instead localized at the M-band <ref name="c" />; It has also been reported that telethonin interacts with other proteins including potassium channel β-subunit of the slow activating component of the delayed rectifier potassium current (IKs) channel (minK) <ref name="d"> PMID:11697903 </ref>, Ankyrin1 <ref>PMID:12444090 </ref>, and Z-disk proteins [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:Myozenin FATZ,/Myozenin-1/ Calsarcin-3] <ref name="e"> PMID:11842093 </ref>, and Ankrd2.<ref name="f"> PMID:15136035 </ref>

Telethonin interacts with minK’s cytoplasmic domain, and minK binds specifically to the sixteen C-terminal residues of telethonin. This suggests that minK, telethonin and titin form a complex that links myofibrils to the sarcolemma. This process can be negatively regulated by the phosphorylation of telethonin on Ser157. This interaction has been shown to occur in cardiac myofibrils, but it has not been reported to exist in skeletal muscle, where minK is not expressed. <ref name="d" />.

Telethonin interacts with the N-terminus of FATZ/Myozenin-1/Calsarcin-2 between residues 78-125. This interaction may play a role in mechanosensation and stretch-associated signaling. <ref name="e" /> As part of the mechanical stress/stretch sensor machinery, telethonin interacts with Ankrd2, to transmit the signal to the nucleus so Ankrd2 can regulate gene expression. <ref name="f" />

Telethonin is also involved in signalling processes that regulate muscle development. A feed back loop is formed with Myogenic Regulatory Factors (MyoD, myogenin, Myf5), telethonin and myostatin. MyoD possitively regulates telethonin, which then inhibits myostatin by direct interaction. While ‘’MyoD’’ expression is repressed by the myostatin-Smad3 pathway, repression of ‘’MyoD’’ itself is lost when myostatin is inhibited by telethonin. <ref>PMID:18440815</ref> <ref>PMID:12209887</ref>

Telethonin is inhibited by MDM2 in a dose dependent manner, MDM2 N-terminus interacts with telethonin and redirects it to the nucleus. In cells MDM2 is involved in the regulation of proteasomal turnover of telethonin. <ref name="a" />

One interaction that is associated with pathology is with bone morphogenetic protein-10 (BMP10). The interaction between telethonin and BMP10 is thought to act as a sensor of increased wall stress of the left ventricle. A BMP10 variant is associated with hypertension dilated cardiomyopathy. In this case, BMP10 binding to telethonin is reduced, and its extracellular secretion is increased, causing cardiomyocyte hypertrophy. <ref>PMID:17921333 </ref>

Yeast two hybrid screens (Y2H) of skeletal muscle cDNA libraries with baits for the E3 ubiquitin ligases MURF1 and MURF2 have shown an interaction with telethonin, suggesting MURF1/2 may target telethonin for degradation by the proteasome. <ref>PMID:15967462 </ref> An interaction between the pro-apototic protein Siva and Telethonin has also shown by Y2H, and verified by ‘’in-vitro’’ pull-down assays, and immunoflurescence experiments showing a colocalization of both proteins in transfected HEK293 cells, but not yet confirmed ‘’in-vivo’’. <ref>PMID:18849585</ref>

Finally, the catalyitic domain of Protein Kinase D (PKD) has been shown to interact with telethonin. Telethonin has the PKD recognition motif Arg-X-X-Ser, suggesting PKD may regulate sarcomeric assembly and turnover through phosphorylation of telethonin. <ref>PMID: 155114163 </ref>

== Pathologies associated with Telethonin ==

Different mutations in Telethonin have been associated with several myopathies. Mutations can lead to limb-girdle muscular dystrophy type 2G (LGMD2G) <ref name="g"> PMID:10655062 </ref>, to hypertrophic cardiopathy, <ref name="h"> PMID:12507422 </ref> and dilated cardiomyopathy.

Two mutations found in the ''Tcap'' gene causing deletion of the telethonin C-terminal region and lost of the titin kinase phosphorylation site <ref name="g" />, were reported in Brazilian patients with LGMD2G.

Defects in the MLP-telethonin association have been linked to human dilated cardiomyopathy and heart failure (Knöll 2002). Mutations that affect ability of [http://www.proteopedia.org/wiki/index.php/Group:MUZIC:MLP MLP] to interact with telethonin resulting in the loss of telethonin binding facilitate its mislocalization from the complex with titin, and lead to defects in the Z-disk and progression of dilated cardiomyopathy. Knöll et al. conclude that genetic mutations causing a incorrect interaction between telethonin and MLP can lead to a development of human dilated cardiomyopathy through modifications in the conformation and function of titin. <ref name="h" />

Finally, decreased staining for telethonin in type II fibers, and in early stages of fiber atrophy were reported in 10 cases of neurogenic atrophy, <ref>PMID: 11763198</ref> indicating a selective downregulation of telethonin in these cases. These observations can be corelated to ‘’in-vivo’’ studies of short-term dennervation (two days) in rat skeletal muscle, in which ‘’Tcap’’ mRNA was reduced by about 50%. <ref name="Mason" />.

== References ==

<references/>

Group:MUZIC:Plectin

2013-04-02T11:54:17Z

Nikos Pinotsis: /* Sequence annotation */

== Introduction ==
Plectin is a multidomain protein with large size (>500kDa) and versatile binding properties, which abundantly expressed in a wide variety of mammalian tissues and cell types, combined with different binding partners. It has important functions in maintaining the mechanical stability of skin, skeletal muscle and heart.

The plectin gene has unusual 5'-end diversity, which is alternatively spliced into exon 2 and makes 11 kinds of isoforms.
Expression level of isofroms is varied in tissues,and some of them are specifically expressed in brain (isoform 1c),skeletal muscle (isoform 1d) and skin(isoform 1a). <ref>PMID:10556294</ref>.

[[Image:isoforms.gif]]

<Structure load='3PE0' size='300' frame='true' align='right' caption='Crystal structure of SR4-SR5-SH3 regions in the plakin domain (PDB:3PE0)' scene='User:Jae-Geun_Song/Workbench/plectin/Plakin/1'/>

== Sequence annotation ==
The isoform-1 of the human plectin contains 4,684 amino acids [http://www.uniprot.org/uniprot/Q15149 (uniprot:Q15149)]. Plectin can be divided in three main sections; a central coiled-coil rod domain(exon 31), N and C-terminal globular region and exhibits a dumbbell like structure <ref>PMID:8633055</ref>. C-terminal region (exon 32) is composed of 6 homologous repeating domains, and this region has a role in binding to intermediate filaments such as vimentin and cytokeratin <ref>PMID:3430617</ref>. N-terminal globular region contains actin binding domain comprising two calponin homology (exon 2-8) and plakin domain (exon 9-30).

[[Image:plectin.jpg]]

Schematic domain map of plectin (Winter, 2013)

== Structures ==

'''1. Actin Binding Domain (ABD)'''

<Structure load='1sh6' size='300' frame='true' align='right' caption='The actin binding domain of plectin (PDB:1SH6)' scene='User:Jae-Geun_Song/Workbench/plectin/Plecin_actin_binding_domain/1'/>

Plectin has a canonical actin binding domain in N-terminus, which is consisted of two calponin homology domain(<scene name='User:Jae-Geun_Song/Workbench/plectin/Plecin_actin_binding_domain/3'>CH1 and CH2</scene>)<ref>PMID:9164454</ref>. N-terminal domain of plectin containing ABD interacts with F-actin and regulates actin dynamics in vivo, additionally binding of plectin ABD to vimentin was also reported <ref>PMID: 15128297</ref>.

'''2. Plakin domain'''

The plakin domain is formed by an array of spectrin repeats (SR) and a Src-homology 3 (SH3), and harbors binding sites for junctional proteins. This region is adjacent to the actin-binding domain and is required for efficient binding to the integrin alpha6beta4 in hemidesmosomes.<ref>PMID: 21288893 </ref>

'''3. Integrin β4-Plectin complex'''
The interaction between the integrin α6β4 and plectin is essential for the assembly and stability of hemidesmosomes, which are junctional adhesion complexes that anchor epithelial cells to the basement membrane.<ref>PMID: 19242489 </ref>

== Function and Interactions ==
Proteins coordinate various cytoskeletal networks are termed as cytolinkers, which are able to interlink different types of cytoskeletons. Plectin is one of the well-characterized cytolinker and expressed in diverse cell types and tissues, a number of different binding partners of plectin have been identified.

Intermediate filament(IF) binding sites of plectin is located between plakin repeats 5 and 6 in C-terminal globular domain. Several IF proteins were identified to interact with plectin such as vimentin, desmin, GFAP(glial fibrillary acidic protein) and cytokeratins <ref>PMID: 8830774 </ref> .

The actin binding domain(ABD)in N-terminal globular domain has a role to interact with integrin subunit beta 4 to establish mechanical stability in hemedesmosomes along with its function for binding to actin filament(F-actin). Calmodulin(CaM) is also known to bind the ABD of plectin to modulate the hemidesmosome disassembly <ref> PMID: 19419971 </ref>.

<Structure load='3F7P' size='300' frame='true' align='right' caption='Crystal structure of plectin ABD(magenta) and integrin beta 4 (green) complex (PDB:3F7P)' scene='Group:MUZIC:Plectin/Plecint/1' />

== Pathology ==
It has been reported that patients with EBS-MD (Epidermolysis bullosa simplex with muscular dystrophy),a genetic disorder characterized severe skin blistering disease combined with muscular dystrophy, have a muation on plectin gene(PLEC1). This mutation leads to premature termination of translation.<ref>PMID: 8941634 </ref>
In addition, site-specific missense mutation(R2110W) on plectin rod domain causes an autosomal dominant form of disease termed EBS-Ogna without muscular dystrophy.<ref>PMID: 9067706 </ref>
Plectin deficient(-/-) mice also exhibit similar skin and muscle phenotypes of human patients suffering from EBS-MD and died 2-3 days after birth. <ref>PMID: 9389647</ref>

== References ==

<references/>