Synaptotagmin-binding, cytoplasmic RNA-interacting protein (SYNCRIP), also known as heterogeneous nuclear ribonucleoprotein (hnRNP) Q or NS1-associated protein-1 (NSAP-1), 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 ''SYNCRIP''
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 ...
.
As the name implies, SYNCRIP is localized predominantly in the
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 ...
.
It is evolutionarily
conserved across eukaryotes and participates in several cellular and disease pathways, especially in neuronal and muscular development.
In humans, there are three
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
, all of which are associated ''in vitro'' with pre-
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
s, mRNA splicing intermediates, and mature mRNA-protein complexes, including mRNA turnover.
Structure and function
This gene belongs to the subfamily of ubiquitously expressed
heterogeneous nuclear ribonucleoprotein Heterogeneous nuclear ribonucleoproteins (hnRNPs) are complexes of RNA and protein present in the cell nucleus during gene transcription and subsequent post-transcriptional modification of the newly synthesized RNA (pre-mRNA). The presence of the ...
s (hnRNPs). The hnRNPs are
RNA-binding proteins
RNA-binding proteins (often abbreviated as RBPs) are proteins that bind to the double or single stranded RNA in cells and participate in forming ribonucleoprotein complexes.
RBPs contain various structural motifs, such as RNA recognition motif ...
and they complex with
heterogeneous nuclear RNA
A primary transcript is the single-stranded ribonucleic acid ( RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs ...
(hnRNA).
SYNCRIP is made up of an N-terminal
helix
A helix () is a shape like a corkscrew or spiral staircase. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is formed as two intertwined helices, ...
bundle known as the “acidic domain” (AcD), followed by three sequential
RNA recognition motif
RNA recognition motif, RNP-1 is a putative RNA-binding domain of about 90 amino acids that are known to bind single-stranded RNAs. It was found in many eukaryotic proteins.
The largest group of single strand RNA-binding protein is the eukaryoti ...
s (RRMs) separated by short linkers, and 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 ...
-
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
-rich domain called the “RGG box” at the C-terminus. The RRMs play a role in RNA binding, while the AcD engages in
protein-protein interactions (PPIs). The RGG box is involved in both RNA binding and in PPIs. The AcD is unique to SYNCRIP and its nuclear
homolog
In biology, homology is similarity due to shared ancestry between a pair of structures or genes in different taxa. A common example of homologous structures is the forelimbs of vertebrates, where the wings of bats and birds, the arms of prima ...
hnRNP R, and is involved in interactions with APOBEC-1.
It is a self-folding, all-helical domain of five α-helices, containing a large hydrophobic cavity and a positively charged surface area as potential interaction sites in addition to negatively charged surface areas, with no structural homologs in any other known proteins.
The hydrophobic core is mostly made up of
leucine
Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...
residues, while the surface is made up of 15 acidic residues and 13 basic residues which together form a vast interaction network.
The AcD is linked to RRM1 by a unique α-
β-β unit, creating an “extended RRM fold” mediated primarily by hydrophobic interactions.
The RGG box is an unstructured region containing numerous Arg-Gly-Gly repeats with fairly regular spacing. There are eight such repeats in SYNCRIP. This domain can bind proteins and RNA independently, even if the other binding domains are not present.
Although this domain is rich in arginine content, it does not have any arginine-rich clusters as might be observed in usual arginine-rich RBPs.
Isoform 1 is a component of the
apolipoprotein B
Apolipoprotein B (ApoB) is a protein that in humans is encoded by the gene.
Function
Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, Lp(a), IDL, and LDL particles (LDL—commonly known as "bad cholesterol" when in refer ...
(apoB) mRNA editosome complex, and it modulates the post-transcriptional
C-to-
U 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 organism ...
of apoB mRNA through binding either to the
apoB mRNA-editing enzyme catalytic peptide 1 (APOBEC-1), to the
APOBEC-1 complementation factor (ACF), or directly to RNA itself.
Isoform 1 is also implicated with other RBPs in the cytoplasmic de-adenylation and
translational and decay interplay of
c-Fos mRNA mediated by the major coding-region determinant of instability (mCRD) domain.
The function of isoform 2 is not as clearly understood.
Isoform 3 is involved in cytoplasmic vesicle-based mRNA transport through interaction with
synaptotagmin
Synaptotagmins (SYTs) constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region (TMR), a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 17 isoforms in the mammalian s ...
s (SYTs).
This isoform is also a component of the
gamma interferon (IFNγ)-activated inhibitor of translation (GAIT) complex in humans, which mediates
IFNγ
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
-induced transcript-selective translation inhibition in inflammation processes.
Upon IFN-γ activation, SYNCRIP assembles into the GAIT complex, which binds to
stem-loop
Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence when ...
-containing GAIT elements in the
3’-untranslated region (3’- UTR) of diverse inflammatory mRNAs and suppresses their translation, but this seems to not be essential for the overall function of the GAIT complex.
Interactions
SYNCRIP has been shown to interact with
ACF,
APOBEC1
Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 also known as C->U-editing enzyme APOBEC-1 is a protein that in humans is encoded by the ''APOBEC1'' gene.
This gene encodes a member of the APOBEC protein family and the cytidine de ...
,
[ SYT7,] and SYT9
Synaptotagmin-9 is a protein that in humans is encoded by the ''SYT9'' gene.
Interactions
SYT9 has been shown to interact with SYNCRIP, TUBB and TRPV1
The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as ...
.
References
Further reading
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{{PDB Gallery, geneid=10492