Filamin A, alpha (FLNA) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''FLNA''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Function
Actin-binding protein, or
filamin Filamins are a class of proteins that hold two actin filaments at large angles. Filamin protein in mammals is made up of an actin-binding domain at its N-terminus that is followed by 24 immunoglobulin-like repeat modules of roughly 95 amino acids. ...
, 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
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
and participates in the anchoring of membrane proteins for the actin
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
. 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
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
,
transmembrane receptor complexes, and
secondary messengers
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
. At least 31 disease-causing mutations in this gene have been discovered.
Structure
The protein structure includes an
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
binding N terminal domain, 24 internal repeats and 2 hinge regions.
Interactions
Filamin has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
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) ...
,
*
CD29
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 r ...
*
CASR,
*
FBLIM1
Filamin-binding LIM protein 1 is a protein that in humans is encoded by the ''FBLIM1'' gene.
This gene encodes a protein with an N-terminal filamin-binding domain, a central proline-rich domain, and, multiple C-terminal LIM domains. This protein ...
,
*
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 ...
,
*
FLNB
Filamin B, beta (FLNB), also known as Filamin B, beta (truncated actin binding protein 278 homolog), is a cytoplasmic protein which in humans is encoded by the ''FLNB'' gene.
FLNB regulates intracellular communication and signalling by cross-linki ...
,
*
NPHP1
Nephrocystin-1 is a protein that in humans is encoded by the ''NPHP1'' gene.
Function
This gene encodes a protein with src homology domain 3 (SH3) patterns. Mutations in this gene cause familial juvenile nephronophthisis.
Interactions
NPHP1 ...
,
*
RALA
Ras-related protein Ral-A (RalA) is a protein that in humans is encoded by the ''RALA'' gene on chromosome 7. This protein is one of two paralogs of the Ral protein, the other being RalB, and part of the Ras GTPase family. RalA functions as a molec ...
,
*
SH2B3
SH2B adapter protein 3 (SH2B3), also known as lymphocyte adapter protein (LNK), is a protein that in humans is encoded by the ''SH2B3'' gene on chromosome 12.
SH2B adapter protein 3 is a protein that in humans is encoded by the SH2B3 gene on chrom ...
,
*
TRIO,
and
*
VHL.
RNA editing
The edited residue was previously recorded as a single nucleotide polymorphism(SNP) in
dbSNP
The Single Nucleotide Polymorphism Database (dbSNP) is a free public archive for genetic variation within and across different species developed and hosted by the National Center for Biotechnology Information (NCBI) in collaboration with the Natio ...
.
Type
A to I
RNA editing
RNA editing (also RNA modification) is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase. It occurs in all living organisms ...
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
Guanosine (symbol G or Guo) is a purine nucleoside comprising guanine attached to a ribose (ribofuranose) ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate (GMP), cyclic guanosine monophosphate (c ...
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
Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...
(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
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
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
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
protein is required for efficient regulation of early stages of
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
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
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
and
non-homologous end joining
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...
.
[
]
References
Further reading
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*
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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