Smerdon group ::

Overview:

We are focussed primarily on the roles of phosphorylation - dependent signalling pathways and transcriptional regulation in cell-cycle progression. Signalling processes in eukaryotes are complex and are achieved through combinatorial interactions between arrays of proteins that are often highly modular. These domains may be required for detection of extra- or intra-cellular signals, targeted enzymatic activity, sequence-specific DNA-binding or mediation of interactions with other co-regulatory proteins. Interplay between these protein assemblies is essential for the execution of a successful and correctly timed program of responses. Technological developments have made it increasingly possible to use X-ray crystallography as a biochemical tool which we combine with a broad spectrum of techniques including recombinant DNA methods, limited proteolysis, mass spectrometry, hydrodynamics and NMR spectroscopy to investigate our favourite biological systems. Central to many of our current projects are ongoing external collaborations with Professor Mike Yaffe at the Massachussetts Institute of Technology, and Professor Steve Jackson at the Wellcome/CRUK Institute in Cambridge, UK.

Selected publications ::

• Stucki, M; Clapperton, JA; Mohammad, D; Yaffe, MB; Smerdon, SJ and Jackson, SP (2005)
  MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks.
  Cell 123, 1213-26 PubMed abstract
• Clapperton, JA; Manke, IA; Lowery, DM; Ho, T; Haire, LF; Yaffe, MB and Smerdon, SJ (2004)
  Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer.
  Nature Structural and Molecular Biology 11, 512-8 PubMed abstract
• Yaffe, MB and Smerdon, SJ (2004)
  The use of in vitro peptide-library screens in the analysis of phosphoserine/threonine-binding domain structure and function.
  Annual Review of Biophysics, Biomolecular Structure 33, 225-244 PubMed abstract
• Elia, AEH; Rellos, P; Haire, LF; Chao, JW; Ivins, FJ; Hoepker, K; Mohammad, D; Cantley, LC; Smerdon, SJ and Yaffe, MB (2003)
  The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain.
  Cell 115, 83-95 PubMed abstract
• Li, JJ; Williams, BL; Haire, LF; Goldberg, M; Wilker, E; Durocher, D; Yaffe, MB; Jackson, SP and Smerdon, SJ (2002)
  Structural and functional versatility of the FHA domain in DNA- damage signaling by the tumor suppressor kinase Chk2.
  Molecular Cell 9, 1045-1054 PubMed abstract
• Durocher, D; Taylor, IA; Sarbassova, D; Haire, LF; Westcott, SL; Jackson, SP; Smerdon, SJ and Yaffe, MB (2000)
  The molecular basis of FHA domain : phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms.
  Molecular Cell 6, 1169-1182 PubMed abstract