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 An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

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 An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

. Binding to

phosphotyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is f ...

-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 Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinemia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in diff ...

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 Bioinformatics () is an interdisciplinary field of science Science is a systematic discipline that builds and organises knowledge in the form of testable hypotheses and predictions about the universe. Modern science is typically divi ...

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 In molecular biology, binding domain is a protein domain which binds to a specific atom or molecule, such as calcium or DNA. A protein domain is a part of a protein sequence and a tertiary structure that can change or evolve, function, and live ...

, have been used in

protein engineering Protein engineering is the process of developing useful or valuable proteins through the design and production of unnatural polypeptides, often by altering amino acid sequences found in nature. It is a young discipline, with much research taking pl ...

to create protein assemblies. Protein assemblies are formed when several proteins bind to one another to create a larger structure (called a

supramolecular assembly Supramolecular chemistry refers to the branch of chemistry concerning chemical systems composed of a discrete number of molecules. The strength of the forces responsible for spatial organization of the system range from weak intermolecular forces ...

). 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 Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this ''fusion gene'' r ...

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 Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ''ABL1'' gene (previous symbol ''ABL'') located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammali ...

;

ABL2 Tyrosine-protein kinase ABL2 also known as Abelson-related gene (Arg) is an enzyme that in humans is encoded by the ''ABL2'' gene. Function ABL2 is a cytoplasmic tyrosine kinase which is closely related to but distinct from ABL1. The simila ...

* 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 Chimerin 2 (beta-chimaerin) is a protein that in humans is encoded by the ''CHN2'' gene. This gene is a member of the chimerin family and encodes a protein with a phorbol-ester/diacylglycerol-type zinc finger, a Rho-GAP domain and an SH2 domain ...

; 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 Fer (also known as Fer Servadou, Pinenc, Mansois and several other synonyms) is a red French wine grape variety that is grown primarily in South West France and is most notable for its role in the ''Appellation d'Origine Contrôlée'' (AOC) ...

;

FES Fez () or Fes (; ) is a city in northern inland Morocco and the capital of the Fez-Meknes administrative region. It is one of the largest cities in Morocco, with a population of 1.256 million, according to the 2024 census. Located to the nort ...

; FGR; FRK;

FYN Proto-oncogene tyrosine-protein kinase Fyn (p59-FYN, Slk, Syn, MGC45350, Gene ID 2534) is an enzyme that in humans is encoded by the ''FYN'' gene. Fyn is a 59-kDa member of the Src family of kinases typically associated with T-cell and neurona ...

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 Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the ''GRB10'' gene. Function The product of this gene belongs to a small family of Signal transducing adapto ...

;

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 Growth factor receptor-bound protein 7, also known as GRB7, is a protein that in humans is encoded by the ''GRB7'' gene. Function The product of this gene belongs to a small family of Signal transducing adaptor protein, adaptor proteins that a ...

* HCK; HSH2D *

INPP5D Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1) is an enzyme with phosphatase activity. SHIP1 is structured by multiple domain and is encoded by the ''INPP5D'' gene in humans. SHIP1 is expressed predominantl ...

; INPPL1; ITK;

JAK2 Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF ...

;

LCK Tyrosin-protein kinase Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside lymphocytes and encoded in the human by the ''LCK'' gene. The Lck is a member of Src kinase family (SKF) and is important f ...

; LCP2;

LYN Lyn or LYN may refer to: People * Lyn (singer), South Korean singer * Lyn (gamer), South Korean ''Warcraft III'' player * Lyn (given name) * Lyn (surname) In science and technology * Lynx (constellation), standard abbreviation * Lyn (locomotive ...

* 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 Cytoplasmic protein NCK2 (also known as NCK-beta and Grb4) is a protein that in humans is encoded by the ''NCK2'' gene. Function NCK belongs to family of adaptor proteins. There are two mammalian NCK genes, NCK1 and NCK2. NCK1 is located in c ...

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 Phosphatidylinositol 3-kinase regulatory subunit beta is an enzyme that in humans is encoded by the ''PIK3R2'' gene. A recent study on gene expression indicated that the PIK3R2 gene might have a key role in pan-cancer prognosis. Interactions ...

;

PIK3R3 Phosphatidylinositol 3-kinase regulatory subunit gamma is an enzyme, which in humans is encoded by the ''PIK3R3'' gene. Interactions PIK3R3 has been shown to interact with Insulin-like growth factor 1 receptor, IRS1 and Retinoblastoma protein ...

; PLCG1;

PLCG2 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 is an enzyme that in humans is encoded by the ''PLCG2'' gene. Function From OMIM as of March 24, 2020: Enzymes of the phospholipase C family catalyze the hydrolysis of phos ...

; PTK6;

PTPN11 Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in hu ...

;

PTPN6 Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene. Function The protein encoded by this gene is a member ...

;

RASA1 RAS p21 protein activator 1 or RasGAP (Ras GTPase activating protein), also known as RASA1, is a 120- kDa cytosolic human protein that provides two principal activities: * Inactivation of Ras from its active GTP-bound form to its inactive GDP-b ...

SH2B1 SH2B adapter protein 1 is a protein that in humans is encoded by the ''SH2B1'' gene. Interactions SH2B1 has been shown to interact with: * Grb2, * Insulin receptor, * Janus kinase 2, and * TrkA. Clinical significance Variations close ...

;

SH2B2 SH2B adapter protein 2 is a protein that in humans is encoded by the ''SH2B2'' gene. Function The protein encoded by this gene is expressed in B lymphocytes and contains pleckstrin homology and src homology 2 (SH2) domains. In Burkitt lymphoma ...

; SH2B3;

SH2D1A SH2 domain–containing protein 1A is a protein that in humans is encoded by the ''SH2D1A'' gene. It is often called SLAM-associated protein (symbol SAP), where "SLAM" refers to signaling lymphocytic activation molecules. It is a SH2 domain–con ...

;

SH2D1B SH2 domain-containing protein 1B is a protein that in humans is encoded by the ''SH2D1B'' gene. By binding phosphotyrosines through its free SRC (MIM 190090) homology-2 (SH2) domain, EAT2 regulates signal transduction through receptors expressed ...

;

SH2D2A SH2 domain-containing protein 2A is a protein that in humans is encoded by the ''SH2D2A'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in D ...

;

SH2D3A SH2 domain-containing protein 3A is a protein that in humans is encoded by the ''SH2D3A'' gene. The protein may be useful in Western Blots and ELISAs. Interactions SH2D3A has been shown to interact with the epidermal growth factor receptor ...

; 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 She or S.H.E. may refer to: Language * She (pronoun), the third person singular, feminine, nominative case pronoun in modern English Places * She County, Anhui ** She Prefecture, 589-1121 * She County, Hebei * She River, or Sheshui, Hubei * ...

* SLA; SLA2 *

SOCS1 Suppressor of cytokine signaling 1 is a protein that in humans is encoded by the ''SOCS1'' gene. ''SOCS1'' orthologs have been identified in several mammals for which complete genome data are available. Function This gene encodes a member of t ...

;

SOCS2 Suppressor of cytokine signaling 2 is a protein that in humans is encoded by the ''SOCS2'' gene. This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signalling (SOCS), family. SSI family mem ...

;

SOCS3 Suppressor of cytokine signaling 3 (SOCS3 or SOCS-3) is a protein that in humans is encoded by the ''SOCS3'' gene. This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family ...

;

SOCS4 Suppressor of cytokine signaling 4 is a protein that in humans is encoded by the SOCS4 gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA ...

;

SOCS5 Suppressor of cytokine signaling 5 is a protein that in humans is encoded by the ''SOCS5'' gene. The protein encoded by this gene contains a SH2 domain and a SOCS BOX domain. The protein thus belongs to the suppressor of cytokine signaling (SOCS ...

;

SOCS6 Suppressor of cytokine signaling 6 is a protein that in humans is encoded by the ''SOCS6'' gene. The protein encoded by this gene contains a SH2 domain and a CIS homolog domain. The protein thus belongs to the cytokine-induced STAT inhibitor (CIS ...

;

SOCS7 Suppressor of cytokine signaling 7 is a protein that in humans is encoded by the ''SOCS7'' gene. Interactions SOCS7 has been shown to interact with NCK1 Cytoplasmic protein NCK1 is a protein that in humans is encoded by the ''NCK1'' gene. ...

* 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 Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family. Function All STAT molecules are phosphorylated by receptor associ ...

;

STAT2 Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the ''STAT2'' gene. It is a member of the STAT protein family. This protein is critical to the biological response of type I interferons (IFNs). It funct ...

;

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 Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which ...

;

STAT5A Signal transducer and activator of transcription 5A is a protein that in humans is encoded by the ''STAT5A'' gene. ''STAT5A'' orthologs have been identified in several placentals for which complete genome data are available. Structure STAT5a s ...

;

STAT5B Signal transducer and activator of transcription 5B is a protein that in humans is encoded by the ''STAT5B'' gene. ''STAT5B'' orthologs have been identified in most placentals for which complete genome data are available. Function The protei ...

;

STAT6 Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor c ...

* SUPT6H; SYK * TEC;

TENC1 Tensin-like C1 domain-containing phosphatase is an enzyme that in humans is encoded by the ''TENC1'' gene. The protein encoded by this gene belongs to the tensin family. Tensin is a focal adhesion molecule that binds to actin filaments and partic ...

; TNS;

TNS1 Tensin-1 is a protein that in humans is encoded by the ''TNS1'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to p ...

; TNS3;

TNS4 Tensin-4 is a protein that in humans is encoded by the ''TNS4'' gene. References Further reading

* * * * * * * * * * * * {{gene-17-stub ...

;

TXK TXK (Telephone eXchange Crossbar) was a range of Crossbar exchanges used by the British Post Office telephone network, subsequently BT, between 1964 and 1994. TXC was used as the designation at first, but this was later changed as TXC sounded t ...

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 Guanine nucleotide exchange factor VAV3 is a protein that in humans is encoded by the ''VAV3'' gene. This gene is a member of the VAV gene family. The VAV proteins are guanine nucleotide exchange factors (GEFs) for Rho family GTPases that activ ...

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 ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding ...

References

External links