Edit this page

From Proteopedia

proteopedia linkproteopedia link

The action you have requested is limited to users in the group user.

You can view and copy the source of this page:

{{TOC limit|limit=3}} == '''Filamin C''' == [[Image:Figure 1.png|thumb|Left|400px| '''Figure 1''' Sequence annotation based on the tertiary structure of Human Filamin]] In 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. <ref name="Van der"> PMID 11038172 </ref> Filamin C (also known as FLNc/Gamma-Filamin/ ABPL) 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. Each Ig domain is made of 7 β strands arranged antiparallel in group of 4 and 3 sheets forming a β sandwich. 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. It is noteworthy to mention that the Hinge 1 is alternatively spliced and the majorly expressed variant of FLNc in striated muscles, lacks this hinge <ref> PMID 9791010 </ref>. Also, in FLNc, there is a unique insertion of 80 amino acid residues in domain 20, which is predicted to play a role in Z disc targeting. <ref> PMID 16631741 </ref> As the three Filamin proteins share around 70% homology over the entire sequence with the exception of the hinges <ref name="Flier"> PMID 11336782 </ref>, not many structures of the Filamin C domains exist in the PDB. == '''Sequence''' == The amino-acid sequence of Human Filamin C is available from uniprot [http://www.uniprot.org/uniprot/q14315 uniprot]. The sequence annotation based on the tertiary structure is provided in Figure 1. Note that in Filamin C, Hinge 1 is absent. Also, the evidence for the presence of domain pairs in the C terminal region is only confirmed for FLNa and FLNb. <ref> PMID 19699211 </ref> <ref> PMID 19622754 </ref> <ref> PMID 21636571 </ref> == '''3D Structures''' == So 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. {{Gallery |width=100 |lines=1 |Image:2d7m asym r 500.jpg|[http://proteopedia.org/wiki/index.php/2d7m '''2d7m'''] |Image:1v05 bio r 500.jpg|[http://proteopedia.org/wiki/index.php/1v05 '''1v05'''] |Image:2d7q asym r 500.jpg|[http://proteopedia.org/wiki/index.php/2d7q '''2d7q'''] |Image:2d7n asym r 500.jpg|[http://proteopedia.org/wiki/index.php/2d7n '''2d7n'''] |Image:2nqc bio r 500.jpg|[http://proteopedia.org/wiki/index.php/2nqc '''2nqc'''] |Image:2d7p asym r 500.jpg|[http://proteopedia.org/wiki/index.php/2d7p '''2d7p'''] |Image:2d7o asym r 500.jpg|[http://proteopedia.org/wiki/index.php/2d7o '''2d7o'''] }} [[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 [[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 [[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''' == [[Image:FLN Interaction Annotation.JPG|thumb|Left|700px| '''Figure 2''' Known interactions of Filamin C]] Since its discovery in 1975 as one of the most potent crosslinkers of F- actin <ref> PMID 124734 </ref> , 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. <ref> PMID 23109048 </ref> • Integrin β1A - Domain 19-24 <ref> PMID 16076904 </ref> • Migfilin - Domain 21 <ref> PMID 18829455 </ref> <ref> PMID 19074766 </ref> • [[Group:MUZIC:Myotilin|Myotilin]] - Domain 19-21 <ref name="Van der" /> • FATZ-1 (myozenin-1, calsarcin 2) - Domain 20-24 <ref> PMID 16076904 </ref> • [[Group:MUZIC:Xin |Xin ]] - Domain 20 <ref> PMID 16631741 </ref> • Gamma- and delta-sarcoglycans - Domain 23-24 <ref> PMID 10629222 </ref> • [[Group:MUZIC:Myopodin|Myopodin]] - Domain 19-21 <ref> PMID 20554076 </ref> == '''Pathology''' == Mutations 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) <ref> PMID 15929027 </ref> • Recently an in frame 6 amino acid deletion (Lys899-Val904) and 2 amino acid insertion (Val 899-Cys900) was identified in Ig domain 7 <ref> PMID 20417099 </ref> • And another in frame 4 amino acid (Val930_Thr933) deletion mutation in Ig domain 7 has been found. <ref> PMID 19050726 </ref> • Recently a mutation of 7256C--->T (Thr2419Met) in exon 44 of FLNC coding for domain 22, has been linked to cerebral ataxia in some cases of MFM. <ref> PMID 22806379 </ref> • A mutation of 577G---->A (Ala193Thr)in the Filamin C ABD has been shown to cause dominant distal myopathy <ref> PMID 21620354 </ref> For an extended pathophysiology of the MFM, see <ref> PMID 22961544 </ref> <ref> PMID 23109048 </ref> == '''References''' == <references /> [[Category: Z-disk]]

• Template:Gallery (protected)
• Template:Gallery/aux (protected)
• Template:TOC limit

Return to Main Page.