View source for 3hor


==Structure of the actin-binding domain of human filamin A (reduced)==
<StructureSection load='3hor' size='340' side='right'caption='[[3hor]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3hor]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HOR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HOR FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3hor FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hor OCA], [https://pdbe.org/3hor PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hor RCSB], [https://www.ebi.ac.uk/pdbsum/3hor PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hor ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/FLNA_HUMAN FLNA_HUMAN] Defects in FLNA are the cause of periventricular nodular heterotopia type 1 (PVNH1) [MIM:[https://omim.org/entry/300049 300049]; also called nodular heterotopia, bilateral periventricular (NHBP or BPNH). PVNH is a developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. PVNH1 is an X-linked dominant form. Heterozygous females have normal intelligence but suffer from seizures and various manifestations outside the central nervous system, especially related to the vascular system. Hemizygous affected males die in the prenatal or perinatal period.<ref>PMID:16299064</ref> <ref>PMID:11532987</ref> <ref>PMID:12410386</ref> <ref>PMID:11914408</ref> <ref>PMID:15249610</ref>   Defects in FLNA are the cause of periventricular nodular heterotopia type 4 (PVNH4) [MIM:[https://omim.org/entry/300537 300537]; also known as periventricular heterotopia Ehlers-Danlos variant. PVNH4 is characterized by nodular brain heterotopia, joint hypermobility and development of aortic dilation in early adulthood.  Defects in FLNA are the cause of otopalatodigital syndrome type 1 (OPD1) [MIM:[https://omim.org/entry/311300 311300]. OPD1 is an X-linked dominant multiple congenital anomalies disease mainly characterized by a generalized skeletal dysplasia, mild mental retardation, hearing loss, cleft palate, and typical facial anomalies. OPD1 belongs to a group of X-linked skeletal dysplasias known as oto-palato-digital syndrome spectrum disorders that also include OPD2, Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. FLNA is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. Males with OPD1 have cleft palate, malformations of the ossicles causing deafness and milder bone and limb defects than those associated with OPD2. Obligate female carriers of mutations causing both OPD1 and OPD2 have variable (often milder) expression of a similar phenotypic spectrum.<ref>PMID:12612583</ref> <ref>PMID:15940695</ref>   Defects in FLNA are the cause of otopalatodigital syndrome type 2 (OPD2) [MIM:[https://omim.org/entry/304120 304120]; also known as cranioorodigital syndrome. OPD2 is a congenital bone disorder that is characterized by abnormally modeled, bowed bones, small or absent first digits and, more variably, cleft palate, posterior fossa brain anomalies, omphalocele and cardiac defects.  Defects in FLNA are the cause of frontometaphyseal dysplasia (FMD) [MIM:[https://omim.org/entry/305620 305620]. FMD is a congenital bone disease characterized by supraorbital hyperostosis, deafness and digital anomalies.<ref>PMID:12612583</ref> <ref>PMID:16596676</ref>   Defects in FLNA are the cause of Melnick-Needles syndrome (MNS) [MIM:[https://omim.org/entry/309350 309350]. MNS is a severe congenital bone disorder characterized by typical facies (exophthalmos, full cheeks, micrognathia and malalignment of teeth), flaring of the metaphyses of long bones, s-like curvature of bones of legs, irregular constrictions in the ribs, and sclerosis of base of skull.<ref>PMID:12612583</ref>   Defects in FLNA are the cause of X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX) [MIM:[https://omim.org/entry/300048 300048]. CIIPX is characterized by a severe abnormality of gastrointestinal motility due to primary qualitative defects of enteric ganglia and nerve fibers. Affected individuals manifest recurrent signs of intestinal obstruction in the absence of any mechanical lesion.<ref>PMID:17357080</ref>   Defects in FLNA are the cause of FG syndrome type 2 (FGS2) [MIM:[https://omim.org/entry/300321 300321]. FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation.<ref>PMID:17632775</ref>   Defects in FLNA are the cause of terminal osseous dysplasia (TOD) [MIM:[https://omim.org/entry/300244 300244]. A rare X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin and recurrent digital fibroma during infancy. A significant phenotypic variability is observed in affected females.<ref>PMID:20598277</ref>   Defects in FLNA are the cause of cardiac valvular dysplasia X-linked (CVDX) [MIM:[https://omim.org/entry/314400 314400]. A rare X-linked heart disease characterized by mitral and/or aortic valve regurgitation. The histologic features include fragmentation of collagenous bundles within the valve fibrosa and accumulation of proteoglycans, which produces excessive valve tissue leading to billowing of the valve leaflets.<ref>PMID:17190868</ref>   Note=Defects in FLNA may be a cause of macrothrombocytopenia, a disorder characterized by subnormal levels of blood platelets. Blood platelets are abonormally enlarged.
== Function ==
[https://www.uniprot.org/uniprot/FLNA_HUMAN FLNA_HUMAN] Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton and serves as a scaffold for a wide range of cytoplasmic signaling proteins. Interaction with FLNA may allow neuroblast migration from the ventricular zone into the cortical plate. Tethers cell surface-localized furin, modulates its rate of internalization and directs its intracellular trafficking (By similarity). Involved in ciliogenesis.<ref>PMID:22121117</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ho/3hor_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3hor ConSurf].
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== Publication Abstract from PubMed ==
Filamin A (FLNA) crosslinks F-actin and binds proteins consistent with roles integrating cell signalling and the cytoskeleton. FLNA missense mutations are associated with the otopalatodigital syndrome (OPD) spectrum of skeletal disorders, clustering in discrete domains. One cluster is found in the second calponin homology domain of the FLNA actin-binding domain (ABD), implicating this region as essential for mediating correct function. Here we show that OPD (FLNA E254K) fibroblast lysates have equivalent concentrations of FLNA compared with controls and that recombinant FLNA E254K ABD has increased in vitro F-actin binding (K(d) 13 microm) compared with wild type (WT; K(d) 48 microm). These observations are consistent with a gain-of-function mechanism for OPD. We have determined the crystal structures of the WT and E254K FLNA ABDs at 2.3 A resolution, revealing that they adopt similar closed conformations. The E254K mutation removes a conserved salt bridge but does not disrupt the ABD structure. The solution structures are also equivalent as determined by circular dichroism spectroscopy, but differential scanning fluorimetry denaturation showed reduced stability (decreased T(m) of 5.6 degrees C) for E254K relative to WT. Ex vivo characterization of E254K OPD patient fibroblasts revealed they have similar motility and adhesion as control cells, implying that many core functions mediated by FLNA are unaffected, consistent with OPD only affecting specific tissues despite FLNA being widely expressed. These data provide the first biochemical evidence for a gain-of-function mechanism for the OPD disorders, and mechanistically distinguishes them from the loss-of-function phenotypes that manifest as disorders of neuronal migration.

Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders.,Clark AR, Sawyer GM, Robertson SP, Sutherland-Smith AJ Hum Mol Genet. 2009 Dec 15;18(24):4791-800. Epub 2009 Sep 22. PMID:19773341<ref>PMID:19773341</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3hor" style="background-color:#fffaf0;"></div>

==See Also==
*[[Filamin 3D structures|Filamin 3D structures]]
*[[User:Georg Mlynek/workbench|User:Georg Mlynek/workbench]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Clark AR]]
[[Category: Robertson SP]]
[[Category: Sawyer GM]]
[[Category: Sutherland-Smith AJ]]