||P.326 left column bottom paragraph: "Protein folding in vivo is further complicated by its coupling with translation and by the fact that many newly synthesized polypeptides must be transported into subcellular compartments, such as the endoplasmic reticulum (ER) or the mitochondria (ref 23), prior to folding. The vectorial translation process from the N terminus to C terminus places considerable restrictions on the energy landscape of in vivo folding (refs 24, 25). The exit tunnel of the large ribosomal subunit, ∼100 Å long and ∼20 Å wide, precludes folding beyond the formation of α-helices or small tertiary structural elements that may begin to form near the tunnel exit (refs 26, 27, 28, 29). Thus, the C-terminal 30–40 amino acid residues of the nascent chain cannot participate in the long-range interactions necessary for cooperative domain folding. Consequently, productive folding is delayed until a complete protein domain (∼50–300 amino acid residues), or substantial segments thereof, has emerged from the ribosome (primary sources). Whereas single-domain proteins complete folding posttranslationally (after chain termination and release from the ribosome), proteins consisting of multiple domains may fold cotranslationally as the domains emerge sequentially from the ribosome." See PMID 9237751 p.343 left column: "Proteins generated in this way typically contain two or more domains linked sequentially that are encoded either by distinct exons (in the case of more recently evolved structures, ref 4) or by blocks of exons (ref 2). Importantly, domains (~100–300 amino acids in length) are not only units of function but also represent autonomous structural units of folding (refs 5-7)."