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Sci. Signal., 4 May 2010
Vol. 3, Issue 120, p. ra34
[DOI: 10.1126/scisignal.2000796]

RESEARCH ARTICLES

Loops Govern SH2 Domain Specificity by Controlling Access to Binding Pockets

Tomonori Kaneko1, Haiming Huang1*, Bing Zhao1, Lei Li1, Huadong Liu1, Courtney K. Voss1, Chenggang Wu1, Martin R. Schiller2, and Shawn Shun-Cheng Li1,3{dagger}

1 Department of Biochemistry and the Siebens-Drake Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1.
2 School of Life Sciences, University of Nevada, 4505 Maryland Parkway, Las Vegas, NV 89154–4004, USA.
3 Children’s Health Research Institute, London, Ontario, Canada N6C 2V5.

* Present address: Donnelley Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada M5S 3E1.

Abstract: Cellular functions require specific protein-protein interactions that are often mediated by modular domains that use binding pockets to engage particular sequence motifs in their partners. Yet, how different members of a domain family select for distinct sequence motifs is not fully understood. The human genome encodes 120 Src homology 2 (SH2) domains (in 110 proteins), which mediate protein-protein interactions by binding to proteins with diverse phosphotyrosine (pTyr)-containing sequences. The structure of the SH2 domain of BRDG1 bound to a peptide revealed a binding pocket that was blocked by a loop residue in most other SH2 domains. Analysis of 63 SH2 domain structures suggested that the SH2 domains contain three binding pockets, which exhibit selectivity for the three positions after the pTyr in a peptide, and that SH2 domain loops defined the accessibility and shape of these pockets. Despite sequence variability in the loops, we identified conserved structural features in the loops of SH2 domains responsible for controlling access to these surface pockets. We engineered new loops in an SH2 domain that altered specificity as predicted. Thus, selective blockage of binding subsites or pockets by surface loops provides a molecular basis by which the diverse modes of ligand recognition by the SH2 domain may have evolved and provides a framework for engineering SH2 domains and designing SH2-specific inhibitors.

{dagger} To whom correspondence should be addressed. E-mail: sli{at}uwo.ca

Citation: T. Kaneko, H. Huang, B. Zhao, L. Li, H. Liu, C. K. Voss, C. Wu, M. R. Schiller, S. S. C. Li, Loops Govern SH2 Domain Specificity by Controlling Access to Binding Pockets. Sci. Signal. 3, ra34 (2010).

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