Functions of the SH3 Domain

A primary function of the SH3 domains is to form fimctional oligomeric complexes at defined subcellular sites, frequently in cooperation with other modular domains. SH3 domains are foimd in many proteins associated with the cytoskeleton or with the plasma membrane. Examples are the actin binding protein a-spectrin and myosin lb. Furthermore, SH3 interactions are involved in signal transduction in the Ras pathway (see Chapter 9). 

An example of regulation of enzyme activity via SH3 domains is the negative regulation of the activity of Src tyrosine kinase by SH3-mediated interactions (review Cohen et al 1995). 

The specific function of the SH3 domain is based on increased substrate specificity of tyrosine kinases in this case (Shokat, 1995). In classical enzymes, the substrate binding site and the catalytic center are close together and the substrate binding site is generally highly specific for a particular substrate. The situation is different for tyrosine kinases. Here, the substrate binding site near the catalytic center shows moderate selectivity. The specificity of the reaction is increased, however, by mediation of asso- 

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The Crk protein was first discovered as the transforming principle of the retroviruses CTIO and ASV-1. Abl tyrosine kinase is under discussion as a binding partner of the SH3 domain of Crk (Feller et al., 1994). Possible binding partners of the SH2 domain have been described but their physiological function is unclear. 

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... 

Pawson and Scott, 1997). These modules are 60 amino acids in length and form a five-stranded 3-sandwhich structure Musacchio et al., 1992 Yu et al., 1992 see also the chapter hy Musacchio, this volume) their function is to hind proline-rich sequences in cellular proteins and hence facilitate the assembly of signaling complexes (Koch et al., 1991). A key question for the many proteins which contain hoth SH2 and SH3 domains is whether these domains cooperate in binding. Information regarding this question has been obtained from the structures of SH2-SH3 domain constructs, with the relevant data being the extent of molecular contacts and orientation between the SH2 and the SH3 domains. 

The SH3 fold has been observed in other protein domains with distinct function (relevant information can be found in reference 37). Recently, a group of bacterial proteins bearing significant sequence similarity to the SH3 domain was discovered (38). Whether these prokaryotic domains share the SH3 fold and are involved in PPII recognition is currently unknown. The simplicity of the fold, the great wealth of structural information, and the ease of its biochemical handling have made the SH3 domain a very-well-characterized model system for the study of proteinfolding mechanisms (see for instance references 39-46), but these studies will not be reviewed here. 

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