Prolyl Isomerization in Cellular Folding

The conformation of Xaa-Pro peptide bonds in the newly synthesized polypeptide chains prior to cellular folding is not known. The product of protein biosynthesis could be a uniform chain with all peptide bonds in the trans conformation. If this chain starts to fold immediately, then the trom-prolines would be in the correct conformation already, the cis-prolines would be in the incorrect isomeric state, and their trans — cis isomerization would be involved in the folding of all molecules. Alternatively, if there is sufficient time available for the Xaa-Pro bonds of the nascent chains to reach a cis/trans equilibrium (e.g., when folding is transiently arrested by binding to other proteins, such as heat-shock protein (HSP70), then the distribution of prolyl cis and trans isomers prior to cellular folding could be similar to the distribution found in the unfolded protein in vitro. Such a case was encountered in the maturation 

Prolyl isomerases of the cyclophilin type show some properties that would be expected for a catalyst of cellular protein folding. Cyclophilins occur in all cellular compartments where folding reactions occur. The activity toward accessible prolyl bonds is high, and the specificity with regard to the chemical nature of residue Xaa is low. Additional experiments are clearly needed, however, to clarify the possible role of prolyl isomerases for the in vivo folding process of nascent proteins. 

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