The SH2 (Src Homology 2) domain is a structurally conserved

protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...

contained within the Src oncoprotein and in many other

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

signal-transducing proteins. SH2 domains bind to phosphorylated tyrosine residues on other proteins, modifying the function or activity of the SH2-containing protein. The SH2 domain may be considered the prototypical modular protein-protein interaction domain, allowing the transmission of signals controlling a variety of cellular functions. SH2 domains are especially common in adaptor proteins that aid in the signal transduction of

receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...

pathways.

Structure and interactions

SH2 domains contain about 100 amino acid residues and exhibit a central antiparallel

β-sheet The beta sheet (β-sheet, also β-pleated sheet) is a common structural motif, motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone chain, backbon ...

centered between two α-helices. Binding to phosphotyrosine-containing peptides involves a strictly-conserved Arg residue that pairs with the negatively-charged phosphate on the phosphotyrosine, and a surrounding pocket that recognizes flanking sequences on the target peptide. Compared to other signaling proteins, SH2 domains exhibit only a moderate degree of specificity for their target peptides, due to the relative weakness of the interactions with the flanking sequences. Over 100 human proteins are known to contain SH2 domains. A variety of tyrosine-containing sequences have been found to bind SH2 domains and are conserved across a wide range of organisms, performing similar functions. Binding of a phosphotyrosine-containing protein to an SH2 domain may lead to either activation or inactivation of the SH2-containing protein, depending on the types of interactions formed between the SH2 domain and other domains of the enzyme. Mutations that disrupt the structural stability of the SH2 domain, or that affect the binding of the phosphotyrosine peptide of the target, are involved in a range of diseases including X-linked agammaglobulinemia and severe combined immunodeficiency.

Diversity

SH2 domains are not present in

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...

and appear at the boundary between

protozoa Protozoa (: protozoan or protozoon; alternative plural: protozoans) are a polyphyletic group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic debris. Historically ...

and

animalia Animals are multicellular, eukaryotic organisms in the Biology, biological Kingdom (biology), kingdom Animalia (). With few exceptions, animals heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, ...

in organisms such as the social amoeba ''

Dictyostelium discoideum ''Dictyostelium discoideum'' is a species of soil-dwelling Amoeboid, amoeba belonging to the phylum Amoebozoa, infraphylum Mycetozoa. Commonly referred to as slime mold, ''D. discoideum'' is a eukaryote that transitions from a collection of unic ...

''. A detailed bioinformatic examination of SH2 domains of

human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

and

mouse A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...

reveals 120 SH2 domains contained within 115 proteins encoded by the human genome, representing a rapid rate of evolutionary expansion among the SH2 domains. A large number of SH2 domain structures have been solved and many SH2 proteins have been knocked out in mice.

Applications

SH2 domains, and other binding domains, have been used in protein engineering to create protein assemblies. Protein assemblies are formed when several proteins bind to one another to create a larger structure (called a supramolecular assembly). Using

molecular biology Molecular biology is a branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, biomolecular synthesis, modification, mechanisms, and interactio ...

techniques, fusion proteins of specific enzymes and SH2 domains have been created, which can bind to each other to form protein assemblies. Since SH2 domains require phosphorylation in order for binding to occur, the use of kinase and phosphatase enzymes gives researchers control over whether protein assemblies will form or not. High

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

engineered SH2 domains have been developed and utilized for protein assembly applications. The goal of most protein assembly formation is to increase the efficiency of

metabolic pathways In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical ...

via enzymatic co-localization. Other applications of SH2 domain mediated protein assemblies have been in the formation of high density fractal-like structures, which have extensive molecular trapping properties.Hernández N.E., Hansen W.A., Zhu D., Shea M.E., Khalid M., Manichev V., Putnins M., Chen M., Dodge A.G., Yang L., Marrero-Berríos I., Banal M., Rechani P., Gustafsson T., Feldman L.C., Lee S-.H., Wackett L.P., Dai W., Khare S.D. (2019)
Stimulus-responsive self-assembly of protein-based fractals by computational design
''Nat. Chem''. 2019 11(7): 605-614. Pre-print available at

bioRxiv bioRxiv (pronounced "bio-archive") is an open access preprint repository for the biological sciences co-founded by John Inglis and Richard Sever in November 2013. It was hosted by Cold Spring Harbor Laboratory (CSHL) until March 11, 2025, whe ...

doi: 10.1101/274183.

Examples

Human proteins containing this domain include: * ABL1; ABL2 * BCAR3; BLK; BLNK;

BMX BMX, an abbreviation for bicycle motocross or bike motocross, is a cycle sport performed on BMX bikes, either in competitive BMX racing or freestyle BMX, or else in general street or off-road recreation. History BMX began during the ea ...

; BTK * CHN2; CISH; CRK;

CRKL Crk-like protein is a protein that in humans is encoded by the CRKL gene. Function v-CRK avian sarcoma virus CT10-homolog-like contains one SH2 domain and two SH3 domains. CRKL has been shown to activate the RAS and JUN kinase signaling pat ...

; CSK * DAPP1 * FER; FES; FGR; FRK; FYN *

GRAP GRB2-related adapter protein is a protein that in humans is encoded by the ''GRAP'' gene. This gene encodes a member of the GRB2/Sem5 ('' C. elegans'' homolog)/Drk (''Drosophila'' homolog) family. This member functions as a cytoplasmic signaling ...

;

GRAP2 GRB2-related adapter protein 2 also known as GRB2-related adaptor downstream of Shc (GADS) is a 37 kDa protein that in humans is encoded by the ''GRAP2'' gene. Function This gene encodes a member of the GRB2/Sem5/Drk family. This member is a ...

; GRB10;

GRB14 Growth factor receptor-bound protein 14 is a protein that in humans is encoded by the ''GRB14'' gene. The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and ...

;

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. The protein encoded by this gene binds recepto ...

; GRB7 * HCK; HSH2D * INPP5D; INPPL1; ITK; JAK2; LCK; LCP2; LYN * MATK;

NCK1 Cytoplasmic protein NCK1 is a protein that in humans is encoded by the ''NCK1'' gene. Gene The Nck (non-catalytic region of tyrosine kinase adaptor protein 1) belongs to the adaptor family of proteins. The nck gene was initially isolated fro ...

; NCK2 *

PIK3R1 Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the ''PIK3R1'' gene. Function Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. ...

; PIK3R2; PIK3R3; PLCG1; PLCG2; PTK6; PTPN11; PTPN6; RASA1 * SH2B1; SH2B2; SH2B3; SH2D1A; SH2D1B; SH2D2A; SH2D3A; SH2D3C; SH2D4A; SH2D4B; SH2D5; SH2D6; SH3BP2; SHB;

SHC1 SHC-transforming protein 1 is a protein that in humans is encoded by the ''SHC1'' gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells. SCOP A ( or ) was a poet as represented in Old ...

; SHC3; SHC4; SHD; SHE * SLA; SLA2 * SOCS1; SOCS2; SOCS3; SOCS4; SOCS5; SOCS6; SOCS7 * SRC;

SRMS Canadarm or Canadarm1 (officially Shuttle Remote Manipulator System or SRMS, also SSRMS) is a series of robotic arms that were used on the Space Shuttle orbiters to deploy, manoeuvre, and capture payloads. After the Space Shuttle Columbia disa ...

* STAT1; STAT2;

STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respon ...

; STAT4; STAT5A; STAT5B; STAT6 * SUPT6H; SYK * TEC; TENC1; TNS; TNS1; TNS3; TNS4; TXK *

VAV1 Proto-oncogene vav is a protein that in humans is encoded by the ''VAV1'' gene. Function The protein encoded by this proto-oncogene is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding ...

; VAV2; VAV3 *

YES1 Tyrosine-protein kinase Yes is a Enzyme, non-receptor tyrosine kinase that in humans is encoded by the ''YES1'' gene. This gene is the cellular homolog of the Yamaguchi sarcoma virus oncogene. The encoded protein has tyrosine kinase activity and ...

; ZAP70

References

External links