SH3 domain
Encyclopedia
The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acids residues first identified as a conserved sequence
in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinase
s such as Abl
and Src. It has also been identified in several other protein families such as: PI3 Kinase, Ras
GTPase activating protein, CDC24 and CDC25
. SH3 domains are found in proteins of signaling pathways regulating the cytoskeleton
, the Ras protein, and the Src kinase and many others. They also regulate the activity state of adaptor proteins and other tyrosine kinases and are thought to increase the substrate specificity of some tyrosine kinases by binding far away from the active site
of the kinase
. Approximately 300 SH3 domains are found in proteins encoded in the human genome.
Many SH3-binding epitopes of proteins have a consensus sequence
:
-X-P-p-X-P-
1 2 3 4 5
with 1 and 4 being aliphatic amino acids, 2 and 5 always and 3 sometimes being proline. The sequence binds to the hydrophobic
pocket of the SH3 domain. More recently, SH3 domains that bind to a core consensus motif R-x-x-K have been described. Examples are the C-terminal SH3 domains of adaptor proteins like Grb2 and Mona (a.k.a. Gads, Grap2, Grf40, GrpL etc.). Other SH3 binding motifs have emerged and are still emerging in the course of various molecular studies, highlighting the versatility of this domain.
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
s such as Abl
Abl gene
V-abl Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9.- Function :...
and Src. It has also been identified in several other protein families such as: PI3 Kinase, Ras
Ras superfamily
The Ras superfamily is a protein superfamily of small GTPases, which are all related, to a degree, to the Ras protein subfamily .There are more than a hundred proteins in the Ras superfamily...
GTPase activating protein, CDC24 and CDC25
CDC25
CDC25 can refer to:* Cdc25, a cell division cycle protein* Another name for ras-GRF1, a guanine nucleotide exchange factor...
. SH3 domains are found in proteins of signaling pathways regulating the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
, the Ras protein, and the Src kinase and many others. They also regulate the activity state of adaptor proteins and other tyrosine kinases and are thought to increase the substrate specificity of some tyrosine kinases by binding far away from the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
of the kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
. Approximately 300 SH3 domains are found in proteins encoded in the human genome.
Structure
The SH3 domain has a characteristic beta-barrel fold which consists of five or six β-strands arranged as two tightly packed anti-parallel β sheets. The linker regions may contain short helices. The SH3-type fold is an ancient fold found in eukaryotes as well as prokaryotes.Peptide binding
The classical SH3 domain is usually found in proteins that interact with other proteins and mediate assembly of specific protein complexes, typically via binding to proline-rich peptides in their respective binding partner. Classical SH3 domains are restricted in humans to intracellular proteins, although the small human MIA family of extracellular proteins also contain a domain with an SH3-like fold.Many SH3-binding epitopes of proteins have a consensus sequence
Consensus sequence
In molecular biology and bioinformatics, consensus sequence refers to the most common nucleotide or amino acid at a particular position after multiple sequences are aligned. A consensus sequence is a way of representing the results of a multiple sequence alignment, where related sequences are...
:
-X-P-p-X-P-
1 2 3 4 5
with 1 and 4 being aliphatic amino acids, 2 and 5 always and 3 sometimes being proline. The sequence binds to the hydrophobic
Hydrophobe
In chemistry, hydrophobicity is the physical property of a molecule that is repelled from a mass of water....
pocket of the SH3 domain. More recently, SH3 domains that bind to a core consensus motif R-x-x-K have been described. Examples are the C-terminal SH3 domains of adaptor proteins like Grb2 and Mona (a.k.a. Gads, Grap2, Grf40, GrpL etc.). Other SH3 binding motifs have emerged and are still emerging in the course of various molecular studies, highlighting the versatility of this domain.
Proteins with SH3 domain
- Adaptor proteinAdaptor proteinSignal transducing adaptor proteins are proteins which are accessory to main proteins in a signal transduction pathway. These proteins tend to lack any intrinsic enzymatic activity themselves but instead mediate specific protein–protein interactions that drive the formation of protein complexes...
s - CDC24
- CDC25CDC25CDC25 can refer to:* Cdc25, a cell division cycle protein* Another name for ras-GRF1, a guanine nucleotide exchange factor...
- PI3 kinasePhosphoinositide 3-kinasePhosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
- PhospholipasePhospholipaseA phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...
- Ras GTPase activating protein
- Vav proto-oncogeneVav (protein)Vav is a family of proteins involved in cell signalling. They act as guanine nucleotide exchange factors for small G proteins of the Rho family. GEF activity is mediated via module of tandem DH-PH domains. Vav proteins also appear to exhibit GEF-independent functions.There are three members of...
- GRB2Grb2Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
- p54 S6 kinase 2 (S6K2)Ribosomal s6 kinaseIn molecular biology, ribosomal s6 kinase is a family of protein kinases involved in signal transduction. There are two subfamilies of rsk, p90rsk, also known as MAPK-activated protein kinase-1 , and p70rsk, also known as S6-H1 Kinase or simply S6 Kinase. There are three variants of p90rsk in...