2w0p

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{{STRUCTURE_2w0p| PDB=2w0p | SCENE= }}
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==CRYSTAL STRUCTURE OF THE FILAMIN A REPEAT 21 COMPLEXED WITH THE MIGFILIN PEPTIDE==
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===CRYSTAL STRUCTURE OF THE FILAMIN A REPEAT 21 COMPLEXED WITH THE MIGFILIN PEPTIDE===
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<StructureSection load='2w0p' size='340' side='right' caption='[[2w0p]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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{{ABSTRACT_PUBMED_18829455}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2w0p]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W0P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2W0P FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2j3s|2j3s]], [[2bp3|2bp3]], [[2jf1|2jf1]], [[2brq|2brq]], [[2aav|2aav]]</td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2w0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w0p OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2w0p RCSB], [http://www.ebi.ac.uk/pdbsum/2w0p PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/FLNA_HUMAN FLNA_HUMAN]] Defects in FLNA are the cause of periventricular nodular heterotopia type 1 (PVNH1) [MIM:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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.
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== Function ==
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[[http://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> [[http://www.uniprot.org/uniprot/FBLI1_HUMAN FBLI1_HUMAN]] Serves as an anchoring site for cell-ECM adhesion proteins and filamin-containing actin filaments. Is implicated in cell shape modulation (spreading) and motility. May participate in the regulation of filamin-mediated cross-linking and stabilization of actin filaments. May also regulate the assembly of filamin-containing signaling complexes that control actin assembly. Promotes dissociation of FLNA from ITGB3 and ITGB7. Promotes activation of integrins and regulates integrin-mediated cell-cell adhesion.<ref>PMID:12679033</ref> <ref>PMID:12496242</ref> <ref>PMID:18829455</ref> <ref>PMID:19074766</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/w0/2w0p_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A link between sites of cell adhesion and the cytoskeleton is essential for regulation of cell shape, motility, and signaling. Migfilin is a recently identified adaptor protein that localizes at cell-cell and cell-extracellular matrix adhesion sites, where it is thought to provide a link to the cytoskeleton by interacting with the actin cross-linking protein filamin. Here we have used x-ray crystallography, NMR spectroscopy, and protein-protein interaction studies to investigate the molecular basis of migfilin binding to filamin. We report that the N-terminal portion of migfilin can bind all three human filamins (FLNa, -b, or -c) and that there are multiple migfilin-binding sites in FLNa. Human filamins are composed of an N-terminal actin-binding domain followed by 24 immunoglobulin-like (IgFLN) domains and we find that migfilin binds preferentially to IgFLNa21 and more weakly to IgFLNa19 and -22. The filamin-binding site in migfilin is localized between Pro(5) and Pro(19) and binds to the CD face of the IgFLNa21 beta-sandwich. This interaction is similar to the previously characterized beta 7 integrin-IgFLNa21 interaction and migfilin and integrin beta tails can compete with one another for binding to IgFLNa21. This suggests that competition between filamin ligands for common binding sites on IgFLN domains may provide a general means of modulating filamin interactions and signaling. In this specific case, displacement of integrin tails from filamin by migfilin may provide a mechanism for switching between different integrin-cytoskeleton linkages.
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==Disease==
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Structural basis of the migfilin-filamin interaction and competition with integrin beta tails.,Lad Y, Jiang P, Ruskamo S, Harburger DS, Ylanne J, Campbell ID, Calderwood DA J Biol Chem. 2008 Dec 12;283(50):35154-63. Epub 2008 Sep 30. PMID:18829455<ref>PMID:18829455</ref>
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[[http://www.uniprot.org/uniprot/FLNA_HUMAN FLNA_HUMAN]] Defects in FLNA are the cause of periventricular nodular heterotopia type 1 (PVNH1) [MIM:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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.
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[http://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> [[http://www.uniprot.org/uniprot/FBLI1_HUMAN FBLI1_HUMAN]] Serves as an anchoring site for cell-ECM adhesion proteins and filamin-containing actin filaments. Is implicated in cell shape modulation (spreading) and motility. May participate in the regulation of filamin-mediated cross-linking and stabilization of actin filaments. May also regulate the assembly of filamin-containing signaling complexes that control actin assembly. Promotes dissociation of FLNA from ITGB3 and ITGB7. Promotes activation of integrins and regulates integrin-mediated cell-cell adhesion.<ref>PMID:12679033</ref><ref>PMID:12496242</ref><ref>PMID:18829455</ref><ref>PMID:19074766</ref>
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</div>
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==About this Structure==
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[[2w0p]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W0P OCA].
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==See Also==
==See Also==
*[[Filamin|Filamin]]
*[[Filamin|Filamin]]
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*[[User:Georg Mlynek/workbench|User:Georg Mlynek/workbench]]
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==Reference==
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== References ==
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<ref group="xtra">PMID:018829455</ref><references group="xtra"/><references/>
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Ruskamo, S.]]
[[Category: Ruskamo, S.]]

Revision as of 02:00, 1 October 2014

CRYSTAL STRUCTURE OF THE FILAMIN A REPEAT 21 COMPLEXED WITH THE MIGFILIN PEPTIDE

2w0p, resolution 1.90Å

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