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⇱ Structural basis for phosphoserine-proline recognition by group IV WW domains | Nature Structural & Molecular Biology

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Abstract

Pin1 contains an N-terminal WW domain and a C-terminal peptidyl-prolyl cis-trans isomerase (PPIase) domain connected by a flexible linker. To address the energetic and structural basis for WW domain recognition of phosphoserine (P.Ser)/phosphothreonine (P.Thr)- proline containing proteins, we report the energetic and structural analysis of a Pin1–phosphopeptide complex. The X-ray crystal structure of Pin1 bound to a doubly phosphorylated peptide (Tyr-P.Ser-Pro-Thr-P.Ser-Pro-Ser) representing a heptad repeat of the RNA polymerase II large subunit's C-terminal domain (CTD), reveals the residues involved in the recognition of a single P.Ser side chain, the rings of two prolines, and the backbone of the CTD peptide. The side chains of neighboring Arg and Ser residues along with a backbone amide contribute to recognition of P.Ser. The lack of widespread conservation of the Arg and Ser residues responsible for P.Ser recognition in the WW domain family suggests that only a subset of WW domains can bind P.Ser-Pro in a similar fashion to that of Pin1.

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Figure 1: Overall architecture of human Pin1.
Figure 2: The Pin1–CTD peptide binding interface.
Figure 3: Representative WW domains.

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Acknowledgements

We thank members of the Noel lab and the staff of the Stanford Synchrotron Radiation Laboratory (SSRL) for assistance during data collection at beamline 9-1, R.D. Mullins and L. Blanchoin for guidance with the fluorescence measurements, and S. Richards for assistance with molecular replacement. We are especially grateful to M. Sudol and M.J. Eck for communicating their results prior to publication. The SSRL Biotechnology Program is supported by the National Institutes of Health, National Center for Research Resources, Biomedical Technology Program, and by the Department of Energy, Office of Biological and Environmental Research. This work was supported by a USPHS grant awarded to J.P.N. T.H. is a Frank and Else Schilling American Cancer Society Professor. K.P.L. is a Pew Scholar and a Leukemia Society of America Scholar.

Author information

Authors and Affiliations

  1. Structural Biology Laboratory, University of California, San Diego, La Jolla, 92093, California, USA

    Mark A. Verdecia, Marianne E. Bowman & Joseph P. Noel

  2. Department of Biology, University of California, San Diego, La Jolla, 92093, California, USA

    Mark A. Verdecia

  3. Department of Medicine, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Kun Ping Lu

  4. Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Tony Hunter

Authors
  1. Mark A. Verdecia
  2. Marianne E. Bowman
  3. Kun Ping Lu
  4. Tony Hunter
  5. Joseph P. Noel

Corresponding author

Correspondence to Joseph P. Noel.

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Verdecia, M., Bowman, M., Lu, K. et al. Structural basis for phosphoserine-proline recognition by group IV WW domains. Nat Struct Mol Biol 7, 639–643 (2000). https://doi.org/10.1038/77929

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  • DOI: https://doi.org/10.1038/77929

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