Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

Self-association prompts proteins for new function: The role of altered dynamic properties

Local backbone flexibility along the chain was analyzed in pairs of monomer and homodimeric protein structures with identical sequence. We identified pairs where highly flexible regions (corresponding to prominent peaks in rmsd’s or crystallographic B-factor values) clearly ‘migrate’ to a new location along the polypeptide in the homodimer. We present several systems, where the new flexible region can be linked to the recruitment of a 3rd binding partner, and where this recruitment is not reported for the corresponding monomer. Conformational sampling of these systems over microsecond timescales further confirms the flexibility migration phenomenon. Compelling evidence is provided that altered backbone flexibility in the homodimer state enables specific recruitment of the heterologous binding partner through the process of conformational selection. Our findings lend support to conformational selection as a general mechanism for protein-ligand binding and highlight the regulatory allosteric role played by the homomeric association event itself. There are many examples of allosteric behavior in homo-oligomers, but this is the first time that homomer association is shown to be the binding event that alters binding properties elsewhere in the protein.

Shoshana J. Wodak1
Michael Garton 2
Anatoly Malevanets1
Stephen McKinnon3

1Hospital for Sick Chikdren
Toronto, Canada
2University of Nottingham, UK
3University of Toronto, Canada