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A structural exposé of noncanonical molecular reactivity within the protein tyrosine phosphatase WPD loop

Author

Listed:
  • Huanchen Wang

    (National Institutes of Health)

  • Lalith Perera

    (National Institutes of Health)

  • Nikolaus Jork

    (University of Freiburg)

  • Guangning Zong

    (National Institutes of Health)

  • Andrew M. Riley

    (University of Oxford)

  • Barry V. L. Potter

    (University of Oxford)

  • Henning J. Jessen

    (University of Freiburg)

  • Stephen B. Shears

    (National Institutes of Health)

Abstract

Structural snapshots of protein/ligand complexes are a prerequisite for gaining atomic level insight into enzymatic reaction mechanisms. An important group of enzymes has been deprived of this analytical privilege: members of the protein tyrosine phosphatase (PTP) superfamily with catalytic WPD-loops lacking the indispensable general-acid/base within a tryptophan-proline-aspartate/glutamate context. Here, we provide the ligand/enzyme crystal complexes for one such PTP outlier: Arabidopsis thaliana Plant and Fungi Atypical Dual Specificity Phosphatase 1 (AtPFA-DSP1), herein unveiled as a regioselective and efficient phosphatase towards inositol pyrophosphate (PP-InsP) signaling molecules. Although the WPD loop is missing its canonical tripeptide motif, this structural element contributes to catalysis by assisting PP-InsP delivery into the catalytic pocket, for a choreographed exchange with phosphate reaction product. Subsequently, an intramolecular proton donation by PP-InsP substrate is posited to substitute functionally for the absent aspartate/glutamate general-acid. Overall, we expand mechanistic insight into adaptability of the conserved PTP structural elements.

Suggested Citation

  • Huanchen Wang & Lalith Perera & Nikolaus Jork & Guangning Zong & Andrew M. Riley & Barry V. L. Potter & Henning J. Jessen & Stephen B. Shears, 2022. "A structural exposé of noncanonical molecular reactivity within the protein tyrosine phosphatase WPD loop," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29673-y
    DOI: 10.1038/s41467-022-29673-y
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    References listed on IDEAS

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    1. Danye Qiu & Miranda S. Wilson & Verena B. Eisenbeis & Robert K. Harmel & Esther Riemer & Thomas M. Haas & Christopher Wittwer & Nikolaus Jork & Chunfang Gu & Stephen B. Shears & Gabriel Schaaf & Bernd, 2020. "Analysis of inositol phosphate metabolism by capillary electrophoresis electrospray ionization mass spectrometry," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. Igor Pavlovic & Divyeshsinh T. Thakor & Jessica R. Vargas & Colin J. McKinlay & Sebastian Hauke & Philipp Anstaett & Rafael C. Camuña & Laurent Bigler & Gilles Gasser & Carsten Schultz & Paul A. Wende, 2016. "Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo," Nature Communications, Nature, vol. 7(1), pages 1-8, April.
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