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Group:MUZIC:FilaminC
From Proteopedia
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| - | {{STRUCTURE_1v05| PDB=1v05 | SIZE=300| SCENE= ''User:Ritika_Sethi/workbench/FilaminC/Flnc_ig_24/1'|right|CAPTION=Human Filamin C domain 24}} | ||
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| - | <scene name='User:Ritika_Sethi/workbench/FilaminC/Flnc_ig_24/1'>Human Filamin C domain 24</scene> | ||
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{{<StructureSection load='1v05' size='500' side='left' scene='User:Ritika_Sethi/workbench/FilaminC/Flnc_ig_24/1' caption='Human Filamin C domain 24'>}} | {{<StructureSection load='1v05' size='500' side='left' scene='User:Ritika_Sethi/workbench/FilaminC/Flnc_ig_24/1' caption='Human Filamin C domain 24'>}} | ||
Revision as of 09:09, 29 November 2011
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Filamin CIn humans, 3 isoforms of Filamins exist that are coded by 3 different genes. While the genes for Filamin A and Filamin B are present on the X chromosome and chromosome 3 respectively, and both show a ubiquitous expression in many tissues, gene for Filamin C is located on the Chromosome 7 and the encoded protein is specifically expressed in muscles and has been predicted to have a Z disc targeting motif. [1] Filamin C is an actin binding homodimeric protein composed of two 290 kDa subunits. Each subunit is composed of an α actinin like N terminal actin binding domain (ABD) made up of 2 calponin homology tandem repeats followed by a flexible rod region containing 24 Immunoglobulin like domains (Ig- like) of around 96 residues each. The most C terminal domain (Ig 24) is the self association domain required for its dimerization ability. (Shown on right) The presence of 2 flexible calpain sensitive hinges, Hinge 1 between domain 15 and 16 divides the subunit into Rod 1 and Rod 2 domains and Hinge 2 between 23 and 24 separates the dimerization domain from the rest of domains. Each Ig domain is made of 7 β strands arranged antiparallel in group of 4 and 3 sheets forming a β sandwich. As the three Filamin proteins share around 70% homology over the entire sequence with the exception of the hinges [2], not many structures of the Filamin C domains exist in the PDB.
Sequence
Amino acid sequence of Human Filamin C is available from uniprot. However, the sequence annotation based on the tertiary structure alignment with Dictyostelium gelation factor (ABP-120) [2] is provided here.
3D StructuresSo far, only 7 3 dimensional structures of Filamin C domains exist in the protein database, out which only 2 are solved by X ray crystallography and the rest are solved by NMR. 2nqc - This is a structure of Ig-like domain 23 from human filamin C solved by X ray Crystallography 2d7q - This is a solution structure of the 23th Filamin domain from human Filamin C solved by Solution NMR 2d7m - This is a solution structure of the 14th Filamin domain from human Filamin C solved by Solution NMR 2d7n - This is a solution structure of the 16th Filamin domain from human Filamin C solved by Solution NMR 2d7o - This is a solution structure of the 17th Filamin domain from human Filamin C solved by Solution NMR 2d7p - This is a solution structure of the 22th Filamin domain from human Filamin C solved by Solution NMR 1v05 - This is a structure of the Domain 24 (Dimerization domain) of human Filamin C solved by X ray Crystallography
Functions and interaction partners of Filamin C
Since its discovery in 1975 as one of the most potent crosslinkers of F- actin [3] , major efforts have been focused to elucidate the role of Filamins as scaffolding and signaling molecule in cells. Its major functions include: • Cross linking actin filaments to form Orthogonal branched networks • Physically linking actin cytoskeleton to the membrane • Localization of the membrane receptors and stabilization of the membrane • Serving as scaffold for various interacting proteins which indicates its role in signalling
Some of the major interacting partners are shown in the diagram here. • Integrin β1A - Domain 19-24 [4] • Migfilin - Domain 21 [5] • FATZ-1 (myozenin-1, calsarcin 2) - Domain 20-24[6] • Gamma- and delta-sarcoglycans - Domain 23-24 [8]
PathologyMutations in Filamin C gene form a rare cause Myofibrillar Myopathy (MFM) presenting a wide spectrum of clinical symptoms, mostly involving progressive muscle weakness in all limbs. • First mutation identified in FLNc was in Ig domain 24 (Dimerization domain), caused by a non sense mutation of (8130G-->A; W2710X) [9] • Recently an in frame 6 amino acid deletion (Lys899-Val904) and 2 amino acid insertion (Val 899-Cys900) was identified in Ig domain 7 [10] • And another in frame 4 amino acid (Val930_Thr933) deletion mutation in Ig domain 7 has been found. [11]
References
Extra Reading
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