SH3 domains

SH3 domains bind to proline-rich regions of target molecules... 

Src tyrosine kinases comprise SH2 and SH3 domains in addition to a tyrosine kinase... 

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... 

Figure 13.29 Schematic diagram of the ptoline-tich region of Nef bound to an SH3 domain. The peptide region (red) binds in a groove that extends across the surface of SH3 (green). (Adapted from W. him, Structure 4 6S7-6S9, 1996.)...

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.)...

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). 

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. 

Morton, C.J., et al. Solution structure and peptide binding of the SH3 domain from human Fyn. Structure 4 705-714, 1996. 

WW domains (named after the one letter abbreviation for the amino acid tryptophan) are small regions of around 30 residues, which, like SH3 domains, bind to polyproline sequences. These sequences often contain the consensus sequence PPXY or PPLP. Examples of proteins that contain WW domains include Nedd4 E3 ubiquitin ligase (Fig. 1) and IQGAP1. 

Adaptor protein, containing one SH2 and two SH3 domains, which assembles signaling complexes at receptors and focal adhesions. 

The current understanding on activation of Tec kinases fits into a two-step model. In the first step an intramolecular interaction between the SH3 domain and aproline-rich region in the TH domain is disrupted by binding ofthe PH domain to phosphoinositides, G protein subunits, or the FERM domain of Fak. These interactions lead to conformational changes of Tec and translocation to the cytoplasmic membrane where, in a second step, Src kinases phosphorylate a conserved tyrosine residue in the catalytic domain thereby increasing Tec kinase activity. Autophosphorylation of a tyrosine residue in the SH3 domain further prevents the inhibitory intramolecular interaction resulting in a robust Tec kinase activation. 

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