This entry represents the C-terminal SH3 domain found in the CRK family members []. CRK adaptor proteins consists of SH2 and SH3 domains, which bind tyrosine-phosphorylated peptides and proline-rich motifs, respectively. They function downstream of protein tyrosine kinases in many signaling pathways started by various extracellular signals, including growth and differentiation factors. Cellular CRK (c-CRK) contains a single SH2 domain, followed by N-terminal and C-terminal SH3 domains. It is involved in the regulation of many cellular processes including cell growth, motility, adhesion, and apoptosis. CRK has been implicated in the malignancy of various human cancers [, ]. The C-terminal SH3 domain of CRK has not been shown to bind any target protein; it acts as a negative regulator of CRK function by stabilizing a structure that inhibits the access by target proteins to the N-terminal SH3 domain [].
This entry represents the N-terminal SH3 domain found in the CRK family members []. CRK adaptor proteins consists of SH2 and SH3 domains, which bind tyrosine-phosphorylated peptides and proline-rich motifs, respectively. They function downstream of protein tyrosine kinases in many signaling pathways started by various extracellular signals, including growth and differentiation factors. Cellular CRK (c-CRK) contains a single SH2 domain, followed by N-terminal and C-terminal SH3 domains. It is involved in the regulation of many cellular processes including cell growth, motility, adhesion, and apoptosis. CRK has been implicated in the malignancy of various human cancers [, ]. The N-terminal SH3 domain of CRK binds a number of target proteins including DOCK180, C3G, SOS, and cABL []. The CRK family includes two alternatively spliced protein forms, CRKI and CRKII, that are expressed by the CRK gene, and the CRK-like (CRKL) protein, which is expressed by a distinct gene (CRKL). CrkI lacks the regulatory phosphorylation site and C-terminal SH3 domain present in CrkII and CrkL [, ]. The N-terminal SH3 domain of CRKII has been shown to bind the recognizes proline-rich motifs (PRMs) found in cABL kinase; this interaction is involved in the regulation of cell spreading, microbial pathogenesis, and cancer metastasis [].
Ginkbilobin-2 (Gnk2) is an antifungal protein found in the endosperm of Ginkgoseeds, which inhibits the growth of phytopathogenic fungi such as Fusariumoxysporum. Gnk2 has considerable homology (~85%) to embryo-abundant proteins(EAP) from the gymnosperms Picea abies and P. glauca. Plant EAP are expressedin the late stage of seed maturation and are involved in protection againstenvironmental stresses such as drought. The sequence of Gnk2 is also 28-31%identical to the extracellular domain of cysteine-rich receptor-like kinases(CRK) from the angiosperm Arabidopsis. The CRK members are induced by pathogeninfection and treatment with reactive oxygen species or salicylic acid and areinvolved in the hypersensitive reaction, which is a typical system ofprogrammed cell death. In addition, there are at least 60 genes in Arabidopsisencoding the cysteine-rich secreted proteins (CRSP) with an Gnk2-homologousdomain. Therefore, the proteins with a Gnk2-homologous domain are regarded asone of the largest protein superfamilies, although the role of the conservedGnk2-homologous domain remains unclear [, ].The Gnk2-homologous domain is composed of two α-helices and a fivestranded β-sheet, which forms a compact single-domain architecture with analpha+β-fold. It contains a C-X(8)-C-X(2)-C motif.Cysteine residues form three intramolecular disulphide bridges: C1-C5, C2-C3,and C4-C6 [].
Ginkbilobin-2 (Gnk2) is an antifungal protein found in the endosperm of Ginkgoseeds, which inhibits the growth of phytopathogenic fungi such as Fusariumoxysporum. Gnk2 has considerable homology (~85%) to embryo-abundant proteins(EAP) from the gymnosperms Picea abies and P. glauca. Plant EAP are expressedin the late stage of seed maturation and are involved in protection againstenvironmental stresses such as drought. The sequence of Gnk2 is also 28-31%identical to the extracellular domain of cysteine-rich receptor-like kinases(CRK) from the angiosperm Arabidopsis. The CRK members are induced by pathogeninfection and treatment with reactive oxygen species or salicylic acid and areinvolved in the hypersensitive reaction, which is a typical system ofprogrammed cell death. In addition, there are at least 60 genes in Arabidopsisencoding the cysteine-rich secreted proteins (CRSP) with an Gnk2-homologousdomain. Therefore, the proteins with a Gnk2-homologous domain are regarded asone of the largest protein superfamilies, although the role of the conservedGnk2-homologous domain remains unclear [, ].The Gnk2-homologous domain is composed of two α-helices and a fivestranded β-sheet, which forms a compact single-domain architecture with analpha+β-fold. It contains a C-X(8)-C-X(2)-C motif.Cysteine residues form three intramolecular disulphide bridges: C1-C5, C2-C3,and C4-C6 [].
The Src homology 2 (SH2) domain is a protein domain of about 100 amino-acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps []. Similar sequences were later found in many other intracellular signal-transducing proteins []. SH2 domains function as regulatory modules of intracellular signalling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific, SH2 domains recognise between 3-6 residues C-terminal to the phosphorylated tyrosine in a fashion that differs from one SH2 domain to another, and strictly phosphorylation-dependent manner [, , , ]. They are found in a wide variety of protein contexts e.g., in association with catalytic domains of phospholipase Cy (PLCy) and the non-receptor protein tyrosine kinases; within structural proteins such as fodrin and tensin; and in a group of small adaptor molecules, i.e Crk and Nck. The domains are frequently found as repeats in a single protein sequence and will then often bind both mono- and di-phosphorylated substrates. The structure of the SH2 domain belongs to the α+β class, its overall shape forming a compact flattened hemisphere. The core structural elements comprise a central hydrophobic anti-parallel β-sheet, flanked by 2 short α-helices. The loop between strands 2 and 3 provides many of the binding interactions with the phosphate group of its phosphopeptide ligand, and is hence designated the phosphate binding loop, the phosphorylated ligand binds perpendicular to the β-sheet and typically interacts with the phosphate binding loop and a hydrophobic binding pocket that interacts with a pY+3 side chain. The N- and C-termini of the domain are close together in space and on the opposite face from the phosphopeptide binding surface and it has been speculated that this has facilitated their integration into surface-exposed regions of host proteins [].
The Src homology 2 (SH2) domain is a protein domain of about 100 amino-acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps []. Similar sequences were later found in many other intracellular signal-transducing proteins []. SH2 domains function as regulatory modules of intracellular signalling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific, SH2 domains recognise between 3-6 residues C-terminal to the phosphorylated tyrosine in a fashion that differs from one SH2 domain to another, and strictly phosphorylation-dependent manner [, , , ]. They are found in a wide variety of protein contexts e.g., in association with catalytic domains of phospholipase Cy (PLCy) and the non-receptor protein tyrosine kinases; within structural proteins such as fodrin and tensin; and in a group of small adaptor molecules, i.e Crk and Nck. The domains are frequently found as repeats in a single protein sequence and will then often bind both mono- and di-phosphorylated substrates. The structure of the SH2 domain belongs to the α+β class, its overall shape forming a compact flattened hemisphere. The core structural elements comprise a central hydrophobic anti-parallel β-sheet, flanked by 2 short α-helices. The loop between strands 2 and 3 provides many of the binding interactions with the phosphate group of its phosphopeptide ligand, and is hence designated the phosphate binding loop, the phosphorylated ligand binds perpendicular to the β-sheet and typically interacts with the phosphate binding loop and a hydrophobic binding pocket that interacts with a pY+3 side chain. The N- and C-termini of the domain are close together in space and on the opposite face from the phosphopeptide binding surface and it has been speculated that this has facilitated their integration into surface-exposed regions of host proteins [].
