Workshop V Cell Signaling Networks Presentation Title SH3 domain

							Workshop V: Cell Signaling Networks

Presentation Title: SH3 domain mediated protein-protein interactions.

Speaker:       Brian K. Kay

Institution:   Argonne National Laboratory. Bioscience Division, Bldg. 202
               Argonne, IL 60439 USA

Abstract:
Mediation of protein-protein interaction through modular binding domains, such as SH2, SH3,
PTB, PDZ, WW, or EH domains, is an important mechanism for intracellular signaling. The
physiological importance of one such module, the Src Homology 3 (SH3) domain, is evidenced by
its presence in both the regulators and effectors of the Ras-mediated MAP kinase signaling
pathway. SH3 domain-containing proteins have also been shown to function in a variety of
diverse biological events including cytoskeletal organization, subcellular localization of proteins,
and endocytosis. SH3 domains are known to bind to short proline-rich peptide sequences within
interacting proteins. Typically, the ligands have the consensus sequence, PxxP, and adopt
polyproline type II (PPII) helical structures which fit into shallow hydrophobic pockets, formed by
aromatic residues on the surface of SH3 domains. Furthermore, SH3 domains bind the peptide
ligands in one of two opposite orientations, N- to C-terminus or C- to N-terminus, with the
orientation heavily influenced by interaction between the non-proline residues in the PPII helix
and the residues flanking the main hydrophobic binding surface of the SH3 domain. In this talk, I
will describe how screening phage-displayed combinatorial peptide libraries with SH3 domains
can provide insight into both understanding their molecular recognition properties and the
prediction of their natural cellular ligands.


References:
Kay, B., Williamson, M., and Sudol, M. (2000). The importance of being proline: the interaction
of proline-rich motifs in signalling proteins with their cognate domains. FASEB J. 14, 231-241.

Kay, B. K., Kasanov, J., Knight, S., and Kurakin, A. (2000). Convergent evolution with
combinatorial peptides. FEBS Lett. 480, 55-62.

Tong, A. H., Drees, B., Nardelli, G., Bader, G. D., Brannetti, B., Castagnoli, L., Evangelista, M.,
Ferracuti, S., Nelson, B., Paoluzi, S., Quondam, M., Zucconi, A., Hogue, C. W., Fields, S., Boone,
C., and Cesareni, G. (2002). A combined experimental and computational strategy to define
protein interaction networks for peptide recognition modules. Science 295, 321-4.