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Publication Abstract from PubMed

Molecular chaperones often possess functional modules that are specialized in assisting the formation of specific structural elements, such as disulfide bridges and peptidyl-prolyl bonds in the cis form, in the client protein. A ribosome-associated molecular chaperone called trigger factor (TF), which has a peptidyl-prolyl cis/trans isomerase (PPIase) domain, acts as a highly efficient catalyst in the folding process limited by peptidyl-prolyl isomerization. Herein, we report on the mechanism through which TF recognizes the proline residue in the unfolded client protein during the cis/trans isomerization process. The solution structure of TF in complex with the client protein revealed that TF recognizes proline-aromatic motif located in the hydrophobic stretch of the unfolded client protein through its conserved hydrophobic cleft, suggesting that TF preferentially accelerates the isomerization of the peptidyl-prolyl bond that is eventually folded into the core of the protein in its native fold. Molecular dynamics simulation revealed that TF exploits the backbone amide group of Ile195 to form an intermolecular hydrogen bond with the carbonyl oxygen of the amino acid residue preceding the proline residue at the transition state. This intermolecular hydrogen bond presumably stabilizes the transition state and thus accelerates the isomerization. The importance of such intermolecular hydrogen bond formation during the catalysis was further corroborated by activity assays and NMR relaxation analysis. Our results suggest that both the intermolecular hydrogen bond at the transition state and the hydrophobic environment around the peptidyl-prolyl bond in the client protein play major roles in TF-mediated proline cis/trans isomerization.

Structural insight into proline cis/trans isomerization of unfolded proteins catalyzed by the Trigger Factor chaperone.,Kawagoe S, Nakagawa H, Kumeta H, Ishimori K, Saio T J Biol Chem. 2018 Aug 9. pii: RA118.003579. doi: 10.1074/jbc.RA118.003579. PMID:30093407^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.