Expert Reviews in Molecular Medicine

 



Review Article

SH2 domains: role, structure and implications for molecular medicine


Gabriel Waksman pres1p1c1, Sangaralingam Kumaran a2 and Olga Lubman a3
pres1 Current address: Institute of Structural Molecular Biology at Birkbeck/UCL, Birkbeck College, School of Crystallography, Malet Street, London, WC1E 7HX, and University College London, Department of Biochemistry and Molecular Biology, Gower Street, London, WC1E 6BT, UK.
p1 Previous address: Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, Saint Louis, MO, USA.
a2 Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, 660 South Euclid Avenue, Saint Louis, MO 63110, USA.
a3 Washington University School of Medicine, Department of Molecular Biology and Pharmacology, 660 South Euclid Avenue, Saint Louis, MO 63110, USA.

Abstract

Src homology 2 (SH2) domains are protein modules (of ~100 amino acids) found in many proteins involved in tyrosine kinase signalling cascades. Their function is to bind tyrosine-phosphorylated sequences in specific protein targets. Binding of an SH2 domain to its cognate tyrosine-phosphorylated target links receptor activation to downstream signalling, both to the nucleus to regulate gene expression and throughout the cytoplasm of the cell. This review recapitulates the roles that SH2 domains play in normal and diseased states, describes the successes of SH2 domain research in deciphering their mechanism of action, and provides an overview of the use of SH2 domains as structural templates for the design of inhibitor drugs.


Key Words: Src homology 2; SH2 domain; tyrosine kinase; Src kinase; Syk kinase; phosphotyrosine; thermodynamics; structure.

Correspondence:
c1 Institute of Structural Molecular Biology at Birkbeck/UCL, Birkbeck College, School of Crystallography, Malet Street, London, WC1E 7HX, and University College London, Department of Biochemistry and Molecular Biology, Gower Street, London, WC1E 6BT, UK. Tel: +44 (0) 207 631 6833; Fax: +44 (0) 207 631 6803; E-mail: g.waksman@bbk.ac.uk