The
SRC HOMOLOGY 3 DOMAIN (or
SH3 domain) is a small protein domain of about 60 amino acids residues first identified as a
conserved sequenceIn 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 kinaseA tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Tyrosine kinases are a subgroup of the larger class of protein kinases...
s such as
AblV-abl Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein which 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,
RasRas is a family of genes encoding small GTPases that are involved in cellular signal transduction. Activation of Ras signalling causes cell growth, differentiation and survival...
GTPase activating protein, CDC24 and
CDC25.
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. Approximately 300 SH3 domains are encoded in the human genome. The SH3-type fold is an ancient fold found in eukaryotes as well as prokaryotes. Examples for similar folds are the OB fold, which can, for example, bind to sugars or the HIV DNA Integrase DNA binding domain. Such functionally distinct SH3-like domains often have no recognizable homology on the amino acid level.
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 sequenceIn molecular biology and bioinformatics, a consensus sequence is a way of representing the results of a multiple sequence alignment, where related sequences are compared to each other, and similar functional sequence motifs are found...
:
-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
hydrophobicIn 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.
SH3 domains are found in proteins of signaling pathways regulating the
cytoskeletonThe cytoskeleton is a cellular "scaffolding" or "skeleton" contained within the cytoplasm. The cytoskeleton is present in all cells; it was once thought this structure was 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 catalytic center of the
kinaseIn chemistry and biochemistry, a kinase, alternatively known as a phosphotransferase, is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates. The process is referred to as phosphorylation...
.
Proteins with SH3 domain
- Adaptor protein
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
- CDC25
- PI3 kinase
Phosphoinositide 3-kinases are a family of related intracellular Signal transducer enzymes capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol . They are also known as phosphatidylinositol-3-kinases...
- Phospholipase
A 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 what type of reaction they catalyze:* Phospholipase A...
- Ras GTPase activating protein
- Vav proto-oncogene
- GRB2
Growth 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....
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