Filamin A, alpha (FLNA) is a protein that in humans is encoded by the FLNA gene. [5] [6]
Actin-binding protein, or filamin, is a 280-kD protein that crosslinks actin filaments 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. [7] At least 31 disease-causing mutations in this gene have been discovered. [8]
The protein structure includes an actin binding N terminal domain, 24 internal repeats and 2 hinge regions. [9] [10]
Filamin has been shown to interact with:
The edited residue was previously recorded as a single nucleotide polymorphism(SNP) in dbSNP.
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 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).
The one editing site of FLNA pre-mRNA is located within amino acid 2341 of the final protein. The Glutamine (Q) codon is altered due to a site specific deamination of an adenosine at the editing site to an Arginine (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. [25] 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. [26]
The edited adenosine is located in the 22 immunogloulin[ check spelling ] like repeat of the protein. This region is an integrin β binding domain [27] and a RAC1 binding domain. [20] The amino acid change is likely to effect the electrostatic potential of the binding domains. [25] 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. [28] 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. [25]
The change in electrostatic potential is likely to effect the binding of FLNA to the many proteins it interacts with. [29]
Interaction of FLNA with the BRCA1 protein is required for efficient regulation of early stages of DNA repair processes. [30] FLNA is implicated in the control of the DNA repair process of homologous recombination and non-homologous end joining. [30]
Cortactin is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery. It is present in all cell types. When activated, it will recruit Arp2/3 complex proteins to existing actin microfilaments, facilitating and stabilizing nucleation sites for actin branching. Cortactin is important in promoting lamellipodia formation, invadopodia formation, cell migration, and endocytosis.
Integrin beta-1 (ITGB1), also known as CD29, is a cell surface receptor that in humans is encoded by the ITGB1 gene. This integrin associates with integrin alpha 1 and integrin alpha 2 to form integrin complexes which function as collagen receptors. It also forms dimers with integrin alpha 3 to form integrin receptors for netrin 1 and reelin. These and other integrin beta 1 complexes have been historically known as very late activation (VLA) antigens.
Erbb2 interacting protein (ERBB2IP), also known as erbin, is a protein which in humans is encoded by the ERBB2IP gene. Discovered in 1997, erbin is a 200kDa protein containing a PDZ domain.
Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene.
Disintegrin and metalloproteinase domain-containing protein 12 is an enzyme that in humans is encoded by the ADAM12 gene. ADAM12 has two splice variants: ADAM12-L, the long form, has a transmembrane region and ADAM12-S, a shorter variant, is soluble and lacks the transmembrane and cytoplasmic domains.
Y box binding protein 1 also known as Y-box transcription factor or nuclease-sensitive element-binding protein 1 is a protein that in humans is encoded by the YBX1 gene.
Dynamin-1 is a protein that in humans is encoded by the DNM1 gene.
The double-stranded RNA-specific adenosine deaminase enzyme family are encoded by the ADAR family genes. ADAR stands for adenosine deaminase acting on RNA. This article focuses on the ADAR proteins; This article details the evolutionary history, structure, function, mechanisms and importance of all proteins within this family.
Glutamate ionotropic receptor AMPA type subunit 2 is a protein that in humans is encoded by the GRIA2 gene and it is a subunit found in the AMPA receptors.
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Double-stranded RNA-specific editase 1 is an enzyme that in humans is encoded by the ADARB1 gene. The enzyme is a member of ADAR family.
Filamin B, beta (FLNB), also known as Filamin B, beta , is a cytoplasmic protein which in humans is encoded by the FLNB gene.
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