Folding pathways

Bond C ], K-B Wong, ] Clarke, A R Ferscht and V Daggett 1997. Characterisation of Residual Structure in the Tliermally Denatured State of Barnase by Simulation and Experiment Description of the Folding Pathway. Proceedings of the National Academy of Sciences USA 94 13409-13413. 

Godzik A, J Skolnick and A Kolinski 1992. Simulations of the Folding Pathway of Triose Phosj Lsomerase-type a// Barrel Proteins. Proceedings of the National Academy of Sciences USA 89 1 2633. 

Figure 2.14 shows examples of both cases, an isolated ribbon and a p sheet. The isolated ribbon is illustrated by the structure of bovine trypsin inhibitor (Figure 2.14a), a small, very stable polypeptide of 58 amino acids that inhibits the activity of the digestive protease trypsin. The structure has been determined to 1.0 A resolution in the laboratory of Robert Huber in Munich, Germany, and the folding pathway of this protein is discussed in Chapter 6. Hairpin motifs as parts of a p sheet are exemplified by the structure of a snake venom, erabutoxin (Figure 2.14b), which binds to and inhibits... 

Figure 2.16 Suggested folding pathway from a hairpinlike structure to the Greek key motif. Beta strands 2 and 3 fold over such that strand 2 is aligned adjacent and antiparallel to strand 1. The topology diagram of the Greek key shown here is the same as in Figure 2.15a but rotated 180° in the plane of the page.

Figure 6.2 The molten globule state is an important intermediate in the folding pathway when a polypeptide chain converts from an unfolded to a folded state. The molten globule has most of the secondary structure of the native state but it is less compact and the proper packing interactions in the interior of the protein have not been formed.

Both single and multiple folding pathways have been observed... 

Creighton, T.E. The disulfide folding pathway of BPTl. Science 256 111-114, 1992. 

Levinthal s paradox led protein chemists to hypothesize that proteins must fold by specific folding pathways, and many research efforts have been devoted to the search for these pathways. 

Implicit in the presumption of folding pathways is the existence of intermediate, partially folded conformational states. The notion of intermediate states on the pathway to a tertiary structure raises the possibility that segments of a protein might independently adopt local and well-defined secondary structures (a-helices and /3-sheets). The tendency of a peptide segment to prefer a particular secondary structure depends in turn on its amino acid composition and sequence. 

The corrector activity of 15 was not limited to recombinant systems as it was confirmed in cultured HBE cells isolated from F508del homozygous patients. After 48-h incubation with 6.7 pM 15, a 2-fold increase in forskolin-stimulated chloride current (compared to DMSO-treated cells) or 14% of the response obtained in non-CF-HBE was observed. It was also reported that 14 and 15 increase the cell surface density of other trafficking-deficient proteins, including G601S-hERG. The authors speculate that this class of compounds may act on the folding pathway shared by both misfolded proteins rather than on CFTR itself [16]. 

---