Proline isomerization and its catalysis in protein folding

Abstract

Abstract In proteins the peptide bonds are usually in the trans conformation, which is favoured energetically over cis in both folded and unfolded proteins. However, an appreciable proportion of the peptide bonds preceding proline (prolyl bonds),* and occasionally those preceding other amino acids, arc in the strained cis conformation. These cis peptide bonds create a problem for protein folding. The non-native trans forms predominate at equilibrium in the unfolded or nascent protein molecule and, since cis⇌trans isomerization is an intrinsically slow reaction — because rotation about a partial double bond is required — the rate of folding to the native state is governed by the rate of isomerization. Non-native prolyl isomers do not block the early stages of folding of a protein chain, but they markedly retard the overall folding process. This is clearly seen in the case of small, single-domain proteins. Many of them refold within a few milliseconds when they contain native prolyl isomers, but when non-native isomers are present (in particular trans isomers of bonds that are cis in the native state) folding is retarded from the millisecond to the minute time range.