Group:MUZIC:FilaminC: Difference between revisions
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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> | 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 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. | 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. | 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. | ||
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== '''Sequence''' == | == '''Sequence''' == | ||
[http://www.uniprot.org/uniprot/q14315 | 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''' == | == '''3D Structures''' == | ||
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Some of the major interacting partners are shown in the diagram here. | 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> | • Integrin β1A - Domain 19-24 <ref> PMID 16076904 </ref> | ||
• Migfilin - Domain 21 <ref> PMID 18829455 </ref> | • Migfilin - Domain 21 <ref> PMID 18829455 </ref> <ref> PMID 19074766 </ref> | ||
• [[Group:MUZIC:Myotilin|Myotilin]] - Domain 19-21 <ref name="Van der" /> | • [[Group:MUZIC:Myotilin|Myotilin]] - Domain 19-21 <ref name="Van der" /> | ||
• FATZ-1 (myozenin-1, calsarcin 2) - Domain 20-24<ref> PMID 16076904 </ref> | • FATZ-1 (myozenin-1, calsarcin 2) - Domain 20-24 <ref> PMID 16076904 </ref> | ||
• [[Group:MUZIC:Xin |Xin ]] - Domain 20 <ref> PMID 16631741 </ref> | • [[Group:MUZIC:Xin |Xin ]] - Domain 20 <ref> PMID 16631741 </ref> | ||
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• Gamma- and delta-sarcoglycans - Domain 23-24 <ref> PMID 10629222 </ref> | • Gamma- and delta-sarcoglycans - Domain 23-24 <ref> PMID 10629222 </ref> | ||
• [[Group:MUZIC:Myopodin|Myopodin]] - Domain 19-21 <ref> PMID 20554076 </ref> | • [[Group:MUZIC:Myopodin|Myopodin]] - Domain 19-21 <ref> PMID 20554076 </ref> | ||
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• A mutation of 577G---->A (Ala193Thr)in the Filamin C ABD has been shown to cause dominant distal myopathy <ref> PMID 21620354 </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> | For an extended pathophysiology of the MFM, see <ref> PMID 22961544 </ref> <ref> PMID 23109048 </ref> | ||
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== '''References''' == | == '''References''' == | ||
<references /> | <references /> | ||
[[Category: Z-disk]] | |||