Research ArticleStructural Biology

Loops Govern SH2 Domain Specificity by Controlling Access to Binding Pockets

Science Signaling  04 May 2010:
Vol. 3, Issue 120, pp. ra34
DOI: 10.1126/scisignal.2000796

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Picking the Right Partner

Proteins often interact through motifs or protein domains. Although a particular class of domains generally recognizes a similar motif in their partners, such as the SH2 domain that recognizes proteins containing phosphorylated tyrosine residues, individual members of the domain family also exhibit specificity. Phosphorylation of tyrosine residues is involved in many cell regulatory processes, and particular SH2 domain–containing proteins interact with specific partner proteins upon their phosphorylation. Kaneko et al. address the question of how a particular SH2 domain knows to which phosphorylated tyrosine–containing protein it should bind. In other words, how do the structurally similar SH2 domains exhibit selectivity for particular sequences even though they all contain phosphorylated tyrosine? By examining crystal and solution structures, the authors found that, in addition to a binding pocket for the phosphorylated tyrosine, SH2 domains had three other binding pockets and that loops, which are variable regions of the SH2 domain, controlled the accessibility of these other binding pockets to specify selectivity. With information about the rules governing binding pocket accessibility, the authors switched SH2 domain specificity by engineering key mutations into the loops. Not only does their work suggest a paradigm for understanding the origin of SH2 domain specificity, it also shows that specificity can be engineered, which may be important for rational design of SH2-specific inhibitors and antibodies.