Abstract

REVIEW: Protein Folding in the Cell: On the Mechanisms of Its Acceleration

N. K. Nagradova

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia; fax: (7-095) 939-3181; E-mail: nnagradova@public.mtu.ru

Received November 13, 2003
The mechanisms responsible for protein folding in the cell can be divided in two groups. The ones in the first group would be those preventing the aggregation of unfolded polypeptide chains or of incompletely folded proteins, as well as the mechanisms which provide for the energy-consuming unfolding of incorrectly folded structures, giving them a chance to begin a new folding cycle. Mechanisms of this type do not affect the rate of folding (it occurs spontaneously), yet considerably increase the efficiency of the entire process. By contrast, the mechanisms belonging to second group actually accelerate protein folding by exerting a direct influence on the rate-limiting steps of the overall reaction. Although not a conventional one, such a classification helps define the topic of this review. Its main purpose is to discuss the ability of chaperonins (and that of some chaperones) to interact directly with substrate proteins in the course of their folding and thus accelerate the rate-limiting steps of that process. (Mechanisms of protein folding acceleration produced by the action of enzymes, e.g., peptidyl-prolyl cis/trans isomerase and protein disulfide isomerase, are not considered in this review.) Specific cases demonstrating an accelerated folding of some proteins encapsulated in the bacterial chaperonin GroEL cavity are considered, and the conditions favoring such acceleration are examined. Experimental data supporting the notion that the structure and functional properties of GroEL are not optimal for an effective folding of many of its substrate proteins is discussed. The current status of research on the mechanism behind the active participation of different subunits of eucaryotic cytosol chaperonin (CCT) in the final steps of the folding of actin and tubulin is reviewed. Particular attention is devoted to steric chaperones, which dramatically accelerate the formation of the native structure of their substrate proteins by stabilizing certain folding intermediates. The structural foundations underlying the effect of the subtilisin pro-domain on the folding of the mature enzyme are considered. The prospects of future studies into the mechanisms responsible for accelerating protein folding in the cell are commented upon.
KEY WORDS: protein folding, rate-limiting steps, chaperonins, GroEL, CCT, domains, actin, tubulin, steric chaperones, pro-domains, subtilisin