1. ¹The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
2. ²Biochemistry Department, University of Otago, Dunedin, New Zealand
3. ³Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Australia

Correspondence: CL Day, Department of Biochemistry, University of Otago, 710 Cumberland St, PO Box 56, Dunedin 9001, New Zealand. E-mail catherine.day@stonebow.otago.ac.nz

Received 22 December 2005; Revised 17 February 2006; Accepted 8 March 2006; Published online 28 April 2006.

Abstract

All BH3-only proteins, key initiators of programmed cell death, interact tightly with multiple binding partners and have sequences of low complexity, properties that are the hallmark of intrinsically unstructured proteins (IUPs). We show, using spectroscopic methods, that the BH3-only proteins Bim, Bad and Bmf are unstructured in the absence of binding partners. Detailed sequence analyses are consistent with this observation and suggest that most BH3-only proteins are unstructured. When Bim binds and inactivates prosurvival proteins, most residues remain disordered, only the BH3 element becomes structured, and the short -helical molecular recognition element can be considered to behave as a 'bead on a string'. Coupled folding and binding is typical of many IUPs that have important signaling roles, such as BH3-only proteins, as the inherent structural plasticity favors interaction with multiple targets. This understanding offers promise for the development of BH3 mimetics, as multiple modes of binding are tolerated.