The SRC Homology 3 Domain (or SH3 domain) is a small

protein domain In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...

of about 60

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

residues. Initially, SH3 was described as a

conserved sequence In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids ( DNA and RNA) or proteins across species ( orthologous sequences), or within a genome ( paralogous sequences), or between donor and receptor taxa ...

in the viral adaptor protein v-Crk. This domain is also present in the molecules of phospholipase and several cytoplasmic

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

s such as Abl and Src. It has also been identified in several other protein families such as:

PI3 Kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

Ras Ras or RAS may refer to: Arts and media * RAS Records Real Authentic Sound, a reggae record label * Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service * Rás 1, an Icelandic radio station * Rás 2, an Icelandic radio stati ...

GTPase-activating protein GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are ...

CDC24 The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...

and

cdc25 Cdc25 is a dual-specificity phosphatase first isolated from the yeast '' Schizosaccharomyces pombe'' as a cell cycle defective mutant. As with other cell cycle proteins or genes such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell divis ...

. SH3 domains are found in proteins of signaling pathways regulating the

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 ...

, the

Ras protein Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals ...

, and the

Src kinase Tyrosine-protein kinase CSK also known as C-terminal Src kinase is an enzyme that, in humans, is encoded by the CSK gene. This enzyme phosphorylates tyrosine residues located in the C-terminal end of Src-family kinases (SFKs) including SRC, HC ...

and many others. The SH3 proteins interact with adaptor proteins and tyrosine kinases. Interacting with tyrosine kinases, SH3 proteins usually bind far away from the

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...

. Approximately 300 SH3 domains are found in proteins encoded in the human genome. In addition to that, the SH3 domain was responsible for controlling protein-protein interactions in the

signal transduction pathways Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

and regulating the interactions of proteins involved in the cytoplasmic signaling.

Structure

The SH3 domain has a characteristic

beta-barrel In protein structures, a beta barrel is a beta sheet composed of tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand (hydrogen bond). Beta-strands in many beta-barrels are ...

fold that consists of five or six β-strands arranged as two tightly packed

anti-parallel β sheet In biochemistry, two biopolymers are antiparallel if they run parallel to each other but with opposite directionality (alignments). An example is the two complementary strands of a DNA double helix, which run in opposite directions alongside e ...

s. 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 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 ...

and mediate assembly of specific protein complexes, typically via binding to

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

-rich

peptides Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...

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 In molecular biology and bioinformatics, the consensus sequence (or canonical sequence) is the calculated order of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment. It serves as a simplified r ...

that can be represented as a regular expression or

Short linear motif In molecular biology short linear motifs (SLiMs), linear motifs or minimotifs are short stretches of protein sequence that mediate protein–protein interaction. The first definition was given by Tim Hunt: "The sequences of many proteins contain s ...

: -X-P-p-X-P- 1 2 3 4 5 with 1 and 4 being

aliphatic In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane, ...

amino acids, 2 and 5 always and 3 sometimes being proline. The sequence binds to the

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...

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 interactomes

SH3 domain-mediated protein-protein interaction networks, ''i.e.'', SH3 interactomes, revealed that worm SH3 interactome resembles the analogous yeast network because it is significantly enriched for proteins with roles in endocytosis. Nevertheless, orthologous SH3 domain-mediated interactions are highly rewired between worm and yeast.

Proteins with SH3 domain

Signal transducing adaptor protein Signal transducing adaptor proteins (STAPs) are proteins that are accessory to main proteins in a signal transduction pathway. Adaptor proteins contain a variety of protein-binding modules that link protein-binding partners together and facilitat ...

s *

Cdc25 Cdc25 is a dual-specificity phosphatase first isolated from the yeast '' Schizosaccharomyces pombe'' as a cell cycle defective mutant. As with other cell cycle proteins or genes such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell divis ...

PI3 kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

Phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...

* Ras GTPase-activating protein * Vav proto-oncogene * GRB2 * p54 S6 kinase 2 (S6K2) * SH3D21 *

ARMH3 ARMH3 or Armadillo Like Helical Domain Containing 3, also known as UPF0668 and ''c10orf76'', is a protein that in humans is encoded by the ''ARMH3'' gene. Its function is not currently known, but experimental evidence has suggested that it may be ...

(potentially) * STAC3 * Some

myosins Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility. The first myosin (M2 ...

* SH3 and multiple ankyrin repeat domains:

SHANK1 SH3 and multiple ankyrin repeat domains protein 1 is a protein that in humans is encoded by the ''SHANK1'' gene. Interactions SHANK1 has been shown to interact with: * ARHGEF7, * BAIAP2, * DNM2, * SPTAN1 Alpha II-spectrin, also known as S ...

SHANK2 SH3 and multiple ankyrin repeat domains protein 2 is a protein that in humans is encoded by the ''SHANK2'' gene. Two alternative splice variants, encoding distinct isoforms, are reported. Additional splice variants exist but their full-length natur ...

SHANK3 SH3 and multiple ankyrin repeat domains 3 (Shank3), also known as proline-rich synapse-associated protein 2 (ProSAP2), is a protein that in humans is encoded by the ''SHANK3'' gene on chromosome 22. Additional isoforms have been described for thi ...

YAP1 YAP1 (yes-associated protein 1), also known as YAP or YAP65, is a protein that acts as a transcription coregulator that promotes transcription of genes involved in cellular proliferation and suppressing apoptotic genes. YAP1 is a component in th ...

* ARHGAP12 * vexin ( VXN) * TANGO1 *

Integrase Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage int ...

* Focal Adhesion Kinase (FAK, PTK2) * Proline-rich tyrosine kinase (Pyk2, CADTK, PTK2beta) *

TRIP10 Cdc42-interacting protein 4 is a protein that in humans is encoded by the ''TRIP10'' gene. Interactions TRIP10 has been shown to interact with STAT3, Wiskott-Aldrich syndrome protein, Huntingtin, CDC42, AKAP9 and RHOQ Rho-related GTP-bindi ...

(cip4)

References

External links