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Prolyl cis-trans isomerization as a molecular timer

Nature Chemical Biology volume 3, pages 619–629 (2007)Cite this article

Abstract

Proline is unique in the realm of amino acids in its ability to adopt completely distinct cis and trans conformations, which allows it to act as a backbone switch that is controlled by prolyl cis-trans isomerization. This intrinsically slow interconversion can be catalyzed by the evolutionarily conserved group of peptidyl prolyl cis-trans isomerase enzymes. These enzymes include cyclophilins and FK506-binding proteins, which are well known for their isomerization-independent role as cellular targets for immunosuppressive drugs. The significance of enzyme-catalyzed prolyl cis-trans isomerization as an important regulatory mechanism in human physiology and pathology was not recognized until the discovery of the phosphorylation-specific prolyl isomerase Pin1. Recent studies indicate that both phosphorylation-dependent and phosphorylation-independent prolyl cis-trans isomerization can act as a novel molecular timer to help control the amplitude and duration of a cellular process, and prolyl cis-trans isomerization might be a new target for therapeutic interventions.

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Figure 1: Prolyl cis-trans isomerization as a molecular switch.
Figure 2: Energy diagram for prolyl cis-trans isomerization.
Figure 3: Structural gallery of the four major classes of PPIases.
Figure 4: Phosphorylation-dependent prolyl cis-trans isomerization as a molecular timer in the Neu-Raf-Ras-MAPK signal pathway.
Figure 5: Phosphorylation-independent prolyl cis-trans isomerization as a molecular timer in cell signaling, ion channel gating and phage infection.
Figure 6: Phosphorylation-dependent prolyl cis-trans isomerization as a molecular timer in APP processing and Aβ production in Alzheimer's disease.

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Acknowledgements

We are grateful to the members of the Lu and Nicholson laboratories for stimulating discussions. Work done in the authors' laboratories is supported by US National Science Foundation grant MCB-0641582 and US National Institutes of Health grant AG029385 to L.K.N. and by US National Institutes of Health grants GM58556, AG17870, AG22082 and AG029385 to K.P.L.

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  1. Department of Medicine, Cancer Biology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 1030, Boston, 02215, Massachusetts, USA

    Kun Ping Lu, Greg Finn & Tae Ho Lee

  2. Department of Molecular Biology and Genetics, 239 Biotechnology Building, Cornell University, Ithaca, 14853, New York, USA

    Linda K Nicholson

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Correspondence to Kun Ping Lu.

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Lu, K., Finn, G., Lee, T. et al. Prolyl cis-trans isomerization as a molecular timer. Nat Chem Biol 3, 619–629 (2007). https://doi.org/10.1038/nchembio.2007.35

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