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 o ...

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 ...

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 tax ...

in the

viral Viral means "relating to viruses" (small infectious agents). Viral may also refer to: Viral behavior, or virality Memetic behavior likened that of a virus, for example: * Viral marketing, the use of existing social networks to spread a marke ...

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 cl ...

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 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, Geor ...

and cdc25. 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 comp ...

, the Ras protein, and the Src kinase 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. 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 cellular ...

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

Structure

The SH3 domain has a characteristic beta-barrel fold that 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 that can be represented as a regular expression or Short linear motif: -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, ...

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 facilitate ...

s *

* Cdc25 * PI3 kinase * Phospholipase * Ras GTPase-activating protein * Vav proto-oncogene * GRB2 * p54 S6 kinase 2 (S6K2) *

SH3D21 SH3D21 is a nuclear protein that is encoded by the SH3D21 gene. In humans, this gene is located on chromosome 1 p34.3. The human mRNA transcript is 2527 base pairs and the final protein product is 756 amino acids. While the exact function of ...

* ARMH3 (potentially) * STAC3 * Some myosins * SH3 and multiple ankyrin repeat domains: SHANK1, SHANK2, SHANK3 * YAP1 *

ARHGAP12 Rho GTPase-activating protein 1 is an enzyme that in humans is encoded by the ''ARHGAP1'' gene. Interactions ARHGAP1 has been shown to interact with: * BNIP2 * CDC42, and * RHOA Transforming protein RhoA, also known as Ras homolog family ...

* vexin (

VXN Vexin is a protein encoded by ''VXN'' gene. ''VXN'' is found to be highly expressed in regions of the brain and spinal cord. Gene Location ''VXN'' is found along the plus strand of chromosome 8. The entire gene is 58,522 bp long. ''VXN'' is ...

) * 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 i ...

* Focal Adhesion Kinase (FAK, PTK2) * Proline-rich tyrosine kinase (Pyk2, CADTK, PTK2beta) * TRIP10 (cip4)

References

External links