Filamin A, alpha (FLNA) is a
protein that in humans is encoded by the ''FLNA''
gene.
Function
Actin-binding protein, or
filamin, is a 280-kD protein that crosslinks
actin filaments
Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cells that form part of the cytoskeleton. They are primarily composed of polymers of actin, but are modified by and interact with numerous other pr ...
into orthogonal networks in cortical
cytoplasm and participates in the anchoring of membrane proteins for the actin
cytoskeleton. Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the FLNA gene, is a widely expressed filamin that regulates the reorganization of the actin cytoskeleton by interacting with
integrins,
transmembrane receptor complexes, and
secondary messengers. At least 31 disease-causing mutations in this gene have been discovered.
Structure
The protein structure includes an
actin binding N terminal domain, 24 internal repeats and 2 hinge regions.
Interactions
Filamin has been shown to
interact with:
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BRCA2
''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...
,
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CD29
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CASR,
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FBLIM1,
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FILIP1
Filamin-A-interacting protein 1, abbreviated as FILIP1, is a protein that in humans is encoded by the ''FILIP1'' gene.
Interactions
FILIP1 has been shown to interact with Filamin Filamins are a class of proteins that hold two actin filaments at ...
,
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FLNB,
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NPHP1,
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RALA,
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SH2B3,
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TRIO,
and
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VHL.
RNA editing
The edited residue was previously recorded as a single nucleotide polymorphism(SNP) in
dbSNP.
Type
A to I
RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as
guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR 1 and ADAR 2 being the only enzymatically active members.ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR 2 are widely expressed in tissues while ADAR 3 is restricted to the brain. The double stranded regions of RNA are formed by base-pairing between residues in a region complementary to the region of the editing site. This complementary region is usually found in a neighbouring
intron
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
but can also be located in an exonic sequence. The region that base pairs with the editing region is known as an Editing Complentary Sequence (ECS).
Site
The one editing site of FLNA pre-mRNA is located within amino acid 2341 of the final protein. The
Glutamine (Q)
codon
The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
is altered due to a site specific deamination of an adenosine at the editing site to an
Arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
(R) codon. The editing region is predicted to form a double stranded region of 32 base pairs in length with a complementary sequence about 200 nucleotides downstream of the editing site. This ECS is found in an intronic sequence.
Editing at the Q/R site is likely to involve both ADAR1 and ADAR2.Mice ADAR2 knockouts show a decrease in editing at the Q/R site.ADAR1 double knockouts have no effect on editing.
Structure
The edited adenosine is located in the 22 immunogloulin like repeat of the protein. This region is an
integrin β binding domain
and a
RAC1 binding domain.
The amino acid change is likely to effect the electrostatic potential of the binding domains.
FLNA editing site is 2 nucleotides from a splice site like the R/G site of GluR-2. Both transcripts have 7/8 identical nucleotides around their editing sites. Since it is widely thought that editing at the GLUR-2 Q/R site influences splicing, the sequence and editing site similarity could mean that editing at the FLNA site could also regulate splicing. In vitro experiments of gluR-2 have shown that presence of ADAR2 results in inhibition of splicing.
Analysis of EST data for FLNA show that there is a link between editing of the last exon codon and retention of the following intron.
Function
The change in electrostatic potential is likely to effect the binding of FLNA to the many proteins it interacts with.
DNA repair
Interaction of FLNA with the
BRCA1 protein is required for efficient regulation of early stages of
DNA repair processes.
[Velkova A, Carvalho MA, Johnson JO, Tavtigian SV, Monteiro AN. Identification of Filamin A as a BRCA1-interacting protein required for efficient DNA repair. Cell Cycle. 2010 Apr 1;9(7):1421-33. doi: 10.4161/cc.9.7.11256. Epub 2010 Apr 1. PMID: 20305393; PMCID: PMC3040726] FLNA is implicated in the control of the DNA repair process of
homologous recombination and
non-homologous end joining.
[
]
References
Further reading
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External links
GeneReview/NCBI/NIH/UW entry on Otopalatodigital Spectrum Disorders
GeneReviews/NIH/NCBI/UW entry on X-Linked Periventricular Heterotopia or Bilateral Periventricular Nodular Heterotopia
{{Cytoskeletal proteins
de:Filamin