View source for Group:MUZIC:FilaminC

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== '''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]]