Src tyrosine kinase


Figure 13.26 Schematic diagram of the SH2 domain from the Src tyrosine kinase with bound peptide. The SH2 domain (blue) comprises a central p sheet surrounded by two a helices. Three positively charged residues (green) are involved in binding the phosphotyrosine moiety of the bound peptide (red). (Adapted from G. Waksman et al.. Cell 72 779-790, 1993.) Figure 13.26 Schematic diagram of the SH2 domain from the Src tyrosine kinase with bound peptide. The SH2 domain (blue) comprises a central p sheet surrounded by two a helices. Three positively charged residues (green) are involved in binding the phosphotyrosine moiety of the bound peptide (red). (Adapted from G. Waksman et al.. Cell 72 779-790, 1993.)
Src tyrosine kinases comprise SH2 and SH3 domains in addition to a tyrosine kinase  [c.275]

The polypeptide chain of Src tyrosine kinase, and related family members, comprises an N-terminal "unique" region, which directs membrane association and other as yet unknown functions, followed by a SH3 domain, a SH2 domain, and the two lobes of the protein kinase. Members of this family can be phosphorylated at two important tyrosine residues—one in the "activation loop" of the kinase domain (Tyr 419 in c-Src), the other in a short  [c.275]

Figure 13.30 Ribbon diagram of the structure of Src tyrosine kinase. The structure is divided in three units starting from the N-terminus an SH3 domain (green), an SH2 domain (blue), and a tyrosine kinase (orange) that is divided into two domains and has the same fold as the cyclin dependent kinase described in Chapter 6 (see Figure 6.16a). The linker region (red) between SH2 and the kinase is bound to SH3 in a polyproline helical conformation. A tyrosine residue in the carboxy tail of the kinase is phosphorylated and bound to SH2 in its phosphotyrosine-binding site. A disordered part of the activation segment in the kinase is dashed. (Adapted from W. Xu et al.. Nature 385 595-602, 1997.) Figure 13.30 Ribbon diagram of the structure of Src tyrosine kinase. The structure is divided in three units starting from the N-terminus an SH3 domain (green), an SH2 domain (blue), and a tyrosine kinase (orange) that is divided into two domains and has the same fold as the cyclin dependent kinase described in Chapter 6 (see Figure 6.16a). The linker region (red) between SH2 and the kinase is bound to SH3 in a polyproline helical conformation. A tyrosine residue in the carboxy tail of the kinase is phosphorylated and bound to SH2 in its phosphotyrosine-binding site. A disordered part of the activation segment in the kinase is dashed. (Adapted from W. Xu et al.. Nature 385 595-602, 1997.)
Figure 13.31 Space-filling diagram of Src tyrosine kinase in the same view as Figure 13.30. The SH2 domain makes only a few contacts with the rest of the molecule except for the tail region of the kinase. The SH3 domain contacts the N-domain of the kinase in addition to the linker region. There are extensive contacts between the N- and C-domains of the kinase. (Adapted from W. Xu et al., Nature 385 596-602, 1997.) Figure 13.31 Space-filling diagram of Src tyrosine kinase in the same view as Figure 13.30. The SH2 domain makes only a few contacts with the rest of the molecule except for the tail region of the kinase. The SH3 domain contacts the N-domain of the kinase in addition to the linker region. There are extensive contacts between the N- and C-domains of the kinase. (Adapted from W. Xu et al., Nature 385 596-602, 1997.)
The interaction of the phosphotyrosine tail with SH2 is clearly important for inactivation of the tyrosine kinase, because regulation in vivo is lost upon dephosphorylation or mutation of Tyr 527. The observed interactions of the SH2 and SH3 domains with the linker, the phosphorylated C-terminal tail and the kinase itself, all serve to hold the kinase lobes together, thereby stabilizing ejection of the aC from the catalytic site (see Figure 13.32) as well as holding the activation loop in a conformation that protects Tyr 419 from phosphorylation. A key feature of the assembled regulatory apparatus is the position of the SH3 domain, which binds the linker regions between SH2 and the N-terminal lobe of the kinase and may affect the conformation of aC. Dephosphorylation of tyrosine 527 or recruitment of the SH2 or SH3 domains by strongly binding target molecules abolishes the intermolecular interaction of the linker region and presumably allows helix aC and the activation segment to shift into their active conformations. The SH2 and SH3 domains apparently not only function as adaptors between the kinase and target molecules but are also important for autoregulation of the intrinsic catalytic activity of Src-tyrosine kinases.  [c.278]

Src tyrosine kinases comprise SH2 and SH3  [c.416]

The second group, the tyrosine kinase associated receptors, have cytosolic domains that lack a defined catalytic function. This large and heterogeneous group includes receptors for cytokines as well as for some hormones including growth hormone and prolactin, discussed earlier. These receptors work through associated cytosolic tyrosine kinases, which phosphorylate various target proteins when the receptor binds its ligand. The best characterized of these associated tyrosine kinases are members of the Src family, so called because the first identified member of this family, the transforming agent of Rous sarcoma virus, induces sarcoma tumors of connective tissues. The structure and regulation of Src will be described later in this chapter.  [c.271]

Figure 13.25 (a) Receptor-associated tyrosine kinases frequently contain within their polypeptide chains small modules such as Src homology domains, SH2 or SH3 and pleckstrin homology domains, PH. These modules function as adaptors to bring the kinase to its correct target molecule, (b) SH2 domains bind phosphotyrosine-containing peptide regions of the target molecules, SH3 domains bind proline-rich peptide regions of the target molecules and PH domains are involved in membrane association of kinases with their target molecules.  [c.272]

The structures of many SH3 domains have also been determined as an example, Figure 13.28a shows the SH3 domain from the tyrosine kinase Fyn, a member of the Src family, as determined by the group of Ian Campbell, Oxford University, using NMR methods. The SH3 domain consists of a five-stranded up-and-down antiparallel (3 structure, twisted into a barrel comprising two antiparallel p sheets that pack against each other so that their strands are nearly orthogonal. Strand p2 takes part in both sheets. This fold is common to all SH3 modules. The loop regions differ, however, and in some SH3 domains they contain small regions of secondary structure.  [c.274]

C-terminal lobes of the tyrosine kinase are similar to those of cyclin-depen-dent kinase described in Chapter 6 (see Figure 6.16a), while the SH2 and SH3 domains of Src and Hck have structures very similar to those of the isolated domains (see Figures 13.26 and 13.28a).  [c.277]

Figure 13.32 Regulation of the catalytic activity of members of the Src family of tyrosine kinases, (a) The inactive form based on structure determinations. Helix aC is in a position and orientation where the catalytically important Glu residue is facing away from the active site. The activation segment has a conformation that through steric contacts blocks the catalytically competent positioning of helix aC. (b) A hypothetical active conformation based on comparisons with the active forms of other similar protein kinases. The linker region is released from SH3, and the activation segment changes its structure to allow helix aC to move and bring the Glu residue into the active site in contact with an important Lys residue. Figure 13.32 Regulation of the catalytic activity of members of the Src family of tyrosine kinases, (a) The inactive form based on structure determinations. Helix aC is in a position and orientation where the catalytically important Glu residue is facing away from the active site. The activation segment has a conformation that through steric contacts blocks the catalytically competent positioning of helix aC. (b) A hypothetical active conformation based on comparisons with the active forms of other similar protein kinases. The linker region is released from SH3, and the activation segment changes its structure to allow helix aC to move and bring the Glu residue into the active site in contact with an important Lys residue.
Xu, W., Harrison, S.C., Eck, M.J. Three-dimensional structure of the tyrosine kinase c-Src. Nature 385 595-602, 1997.  [c.281]

C-terminal tail (Tyr 527 in c-Src). Phosphorylation of Tyr 419 activates the kinase phosphorylation of Tyr 527 inhibits it. Crystal structures of a fragment containing the last four domains of two members of this family were reported simultaneously in 1997—cellular Src by the group of Stephen Harrison and Hck by the group of John Kuriyan. The two structures are very similar, as expected since the 440 residue polypeptide chains have 60% sequence identity. The crucial C-proximal tyrosine that inhibits the activity of the kinases was phosphorylated in both cases the activation loop was not.  [c.276]

Src tyrosine kinase contains both an SH2 and an SH3 domain linked to a tyrosine kinase unit with a structure similar to other protein kinases. The phosphorylated form of the kinase is inactivated by binding of a phosphoty-rosine in the C-terminal tail to its own SH2 domain. In addition the linker region between the SH2 domain and the kinase is bound in a polyproline II conformation to the SH3 domain. These interactions lock regions of the active site into a nonproductive conformation. Dephosphorylation or mutation of the C-terminal tyrosine abolishes this autoinactivation.  [c.280]

The inactive state of the kinase is a compact ensemble of the four domains. The SH2 and SH3 domains lie respectively beside the large and small domains of the tyrosine kinase, on the opposite side to the catalytic cleft. The phosphorylated C-terminal tail extends from the base of the large catalytic domain of the kinase into SH2, where the phosphotyrosine is bound in the usual SH2 binding site for phosphotyrosine. The mode of interaction between other residues of this tail and the binding groove of SF12 suggest a low-affinity interaction, because there is no side chain of the tail in the pY+3 pocket that binds He in high-affinity complexes of Src-SF12 (Figure 13.27a). The phosphorylated tail is a short but flexible tether that anchors the SH2 domain to the kinase. Apart from this tail, the SH2 domain makes only a few contacts with the catalytic domain of the kinase (Figure 13.31).  [c.277]

III. Tyr protein kinases A. Cytosolic tyrosine kinases src, fgr, abl, etc.) B. Receptor tyrosine kinases (RTKs) Plasma membrane receptors for hormones such as epidermal growth factor (EGF) or platelet-derived growth factor (PDGE) Raf (a protein kinase)  [c.467]


See pages that mention the term Src tyrosine kinase : [c.281]   
Introduction to protein structure (1999) -- [ c.275 , c.276 ]