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Investigating dynamic interdomain allostery in Pin1

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Abstract

Signaling proteins often sequester complementary functional sites in separate domains. How do the different domains communicate with one another? An attractive system to address this question is the mitotic regulator, human Pin1 (Lu et al., Nature 380:544–547, 1996). Pin-1 consists of two mutually tethered domains: a WW domain for substrate binding and a catalytic domain for peptidyl-prolyl isomerase (PPIase) activity. Pin1 accelerates the cis–trans isomerization of phospho-Ser/Thr-Pro (pS/T-P) motifs within proteins regulating the cell cycle and neuronal development. The early X-ray (Ranganathan et al., Cell 89:875–886, 1997; Verdecia et al., Nat Struct Biol 7:639–643, 2000) and solution NMR studies (Bayer et al., J Biol Chem 278:26183–26193, 2003; Jacobs et al., J Biol Chem 278:26174–26182, 2003) of Pin1 indicated inter- and intradomain motions. We have explored how such motions might affect interdomain communication, using NMR. Our accumulated results indicate substrate binding to Pin1 WW domain changes the intra/interdomain mobility, thereby altering substrate activity in the distal PPIase domain catalytic site. Thus, Pin1 shows evidence of dynamic allostery, in the sense of Cooper and Dryden (Eur J Biochem 11:103–109, 1984). We highlight our results supporting this conclusion and summarize them via a simple speculative model of conformational selection.

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Acknowledgments

JWP thanks Dr. Andrew T. Namanja, Dr. John S. Zintsmaster, Dr. Xingsheng Wang, Dr. Tao Peng, Dr. Jill J. Bouchard, Dr. Kimberly A. Wilson, Dr. Petra Rovó, Mr. Brendan J. Mahoney, Ms. Meiling Zhang, Dr. Jaroslav Zajicek, Dr. Felicia A. Etzkorn (VA Tech), Cheryl L. Schairer, and Shelby L. Peng for perseverance, inspiration, and useful discussions.

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Funding

This work was funded by the National Institutes of Health (NIH) Grant R01-GM083081 (JWP).

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J.W. Peng declares no conflicts of interest.

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This article does not contain any studies with human participants or animal subjects performed by the author.

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  1. Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN, 46556, USA

    Jeffrey W. Peng

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Correspondence to Jeffrey W. Peng.

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This article is part of a Special Issue on 'The Role of Protein Dynamics in Allosteric Effects' edited by Gordon Roberts.

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Peng, J.W. Investigating dynamic interdomain allostery in Pin1. Biophys Rev 7, 239–249 (2015). https://doi.org/10.1007/s12551-015-0171-9

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