APC proteolysis not overdone

JCB • VOLUME 169 • NUMBER 1 • 2005 16 Folding in a crowd roteins fold better in a crowd, as predicted by a biophysical model from Margaret Cheung, Dmitri Klimov, and D. Thirumalai (University of Maryland, College Park, MD). Interactions between a protein and large nearby molecules produce repulsive forces at distances that can be as large as the protein itself. The group modeled the energetic effects of these interactions on folding of a WW domain and found that it folds faster and has a more stable folded state in a crowded environment. The more spread out the protein, the more likely it is to experience unfavorable interactions with macromolecules. Compaction, in contrast, promotes its isolation. Folding rates reach a maximum when 10% of the solution volume is taken up by other large molecules, but even at high densities the folding rates were still well above that in dilute solution. Approximately 40% of a bacterial cell is occupied by macromolecules. Thirumalai suggests that crowding effects may relieve some of the evolutionary pressure to produce rapidly folding sequences. “An optimal design may not be necessary,” he says. “Maybe in fact moderately well-designed amino acid sequences are good enough.” P