Cotranslational protein folding.

The problem of how the linear amino acid sequence of a polypeptide folds to assume its unique tertiary structure is one of the most basic and challenging conundrums of contemporary science. Many of the principles and characteristics of protein folding have been learned by studying refolding of denatured polypeptides. However, the problem of protein folding cannot be completely understood without reference to the biological context of protein folding, especially for large, multidomain, and multisubunit proteins. One of the basic differences between biosynthetic protein folding and protein renaturation is cotranslational folding, folding that occurs during synthesis. The elegant idea that the process of protein folding is concomitant with synthesis was articulated, and experimental testing was begun in the early 1960s (1, 2). Today there is substantial experimental support for the cotranslational folding hypothesis. Both cotranslational and cotranslocational folding, at least when the latter is coupled to translation, share the basic feature of vectorial appearance of the nascent polypeptide from the ribosome or the membrane and the potential initiation of the folding process by the emerging polypeptide. It is true that the same conformations are achieved by polypeptides folded in cells as a consequence of biosynthetic processes and as a result of refolding of the full-length polypeptide from the denatured state. However, identity of the final protein structures does not necessarily mean identity of the pathways leading to their formation (3). It is the kinetics of the folding process that establishes the folding pathway(s) and potential partitioning among different final forms and, ultimately, their relative yields. In fact, the biological function that is shared by all proteins is the ability to fold properly, and this function must be executed efficiently by all proteins prior to any other function. This seems to be the essence of the vectorial folding process. Several general patterns and principles of cotranslational folding are summarized in Figs. 1 and 2.