Polypeptide chain binding proteins: catalysts of protein folding and related processes in cells

Subcellular compartments in which folding and assembly of proteins occur seem to have a set of PCB proteins capable of mediating these and related processes, such as translocation across membranes. When a domain of a polypeptide chain emerges from a ribosome during synthesis or from the distal side of a membrane during translocation, successive segments of the chain are incrementally exposed to solvent and yet are unlikely to be able to fold. This topological restriction on folding likely mandates a need for PCB proteins to prevent aggregation. Catalysis of topologically restricted folding by PCB proteins is likely to involve both an antifolding activity that postpones folding until entire domains are available and, more speculatively, a folding activity resulting from a programmed stepwise release that employs the energy of ATP hydrolysis to ensure a favorable pathway. We are left with a new set of problems. How do proteins fold in cells? What are the sequences or structural signals that dictate folding pathways? The new challenge will be to understand folding as a combination of physical chemistry, enzymology, and cell biology.