SH3 and multiple ankyrin repeat domains protein 2 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 ''SHANK2''
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 ...
.
Two alternative splice variants, encoding distinct
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 ...
, are reported. Additional splice variants exist but their full-
length
Length is a measure of distance. In the International System of Quantities, length is a quantity with dimension distance. In most systems of measurement a base unit for length is chosen, from which all other units are derived. In the Interna ...
nature has not been determined.
Function
This gene encodes a protein that is a member of the Shank family of synaptic proteins that may function as molecular scaffolds in the
postsynaptic density
The postsynaptic density (PSD) is a protein dense ''specialization'' attached to the postsynaptic membrane. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron. The PSD is in ...
(PSD). Shank proteins contain multiple domains for protein-protein interaction, including
ankyrin repeat
The ankyrin repeat is a 33-residue motif in proteins consisting of two alpha helices separated by loops, first discovered in signaling proteins in yeast Cdc10 and ''Drosophila'' Notch. Domains consisting of ankyrin tandem repeats mediate prot ...
s, an
SH3 domain
The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phos ...
, a
PSD-95
PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the ''DLG4'' (discs large homolog 4) gene.
PSD-95 is a member of the membrane-associated guanylate kinase (MA ...
/Dlg/ZO-1 domain, a sterile alpha motif domain, and a proline-rich region. This particular family member contains a
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to ...
, a consensus sequence for cortactin SH3 domain-binding peptides and a sterile alpha motif. The
alternative splicing
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
demonstrated in Shank genes has been suggested as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the PSDs of adult and developing brain.
It is thought that SHANK2 might play a role in
synaptogenesis
Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenes ...
by attaching
metabotropic glutamate receptor
The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate rece ...
s (mGluRs) to an existing pool of
NMDA receptor
The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...
s (NMDA-R), bylinking to the NMDA-R through PSD-95, and the mGluRs through
HOMER1
Homer protein homolog 1 or Homer1 is a neuronal protein that in humans is encoded by the ''HOMER1'' gene. Other names are Vesl and PSD-Zip45.
Structure
Homer1 protein has an N-terminal EVH1 domain, involved in protein interaction, and a C-te ...
.
An alternative hypothesis is that the Homer/Shank/GKAP/PSD-95 assembly mediates physical association of the NMDAR with IP3R/RYR and intracellular Ca2+ stores.
Interactions
SHANK2 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:
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ARHGEF7,
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Cortactin
Cortactin (from "''cortical actin'' binding protein") 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 c ...
,
*
DLG4,
*
DLGAP1
Disks large-associated protein 1 (DAP-1), also known as guanylate kinase-associated protein (GKAP), is a protein that in humans is encoded by the ''DLGAP1'' gene. DAP-1 is known to be highly enriched in synaptosomal preparations of the brain, and p ...
,
[ and
* ]DNM2
Dynamin-2 is a protein that in humans is encoded by the ''DNM2'' gene.
Function
Dynamins represent one of the subfamilies of GTP-binding proteins. These proteins share considerable sequence similarity over the N-terminal portion of the molecul ...
.
Associations with neuropsychiatric disease
Mutations in SHANK2 have been associated with autism spectrum disorder (ASD) and schizophrenia. In particular, heterozygous loss-of-function mutations have a near-complete penetrance in ASD. Neurons generated from people with ASD and SHANK2 mutations develop larger dendritic trees and more synaptic connections than those from healthy controls. In addition, common mutations in SHANK2 have been linked to bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
.
References
Further reading
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External Links
The SHANK2 Foundation
- non-profit supporting families and research into SHANK2 disorders
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