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Redefining the specificity of phosphoinositide-binding by human PH domain-containing proteins

Author

Listed:
  • Nilmani Singh

    (University of Illinois at Urbana-Champaign)

  • Adriana Reyes-Ordoñez

    (University of Illinois at Urbana-Champaign)

  • Michael A. Compagnone

    (University of Illinois at Urbana-Champaign)

  • Jesus F. Moreno

    (University of Illinois at Urbana-Champaign)

  • Benjamin J. Leslie

    (Johns Hopkins University School of Medicine)

  • Taekjip Ha

    (Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University
    Howard Hughes Medical Institute)

  • Jie Chen

    (University of Illinois at Urbana-Champaign)

Abstract

Pleckstrin homology (PH) domains are presumed to bind phosphoinositides (PIPs), but specific interaction with and regulation by PIPs for most PH domain-containing proteins are unclear. Here we employ a single-molecule pulldown assay to study interactions of lipid vesicles with full-length proteins in mammalian whole cell lysates. Of 67 human PH domain-containing proteins initially examined, 36 (54%) are found to have affinity for PIPs with various specificity, the majority of which have not been reported before. Further investigation of ARHGEF3 reveals distinct structural requirements for its binding to PI(4,5)P2 and PI(3,5)P2, and functional relevance of its PI(4,5)P2 binding. We generate a recursive-learning algorithm based on the assay results to analyze the sequences of 242 human PH domains, predicting that 49% of them bind PIPs. Twenty predicted binders and 11 predicted non-binders are assayed, yielding results highly consistent with the prediction. Taken together, our findings reveal unexpected lipid-binding specificity of PH domain-containing proteins.

Suggested Citation

  • Nilmani Singh & Adriana Reyes-Ordoñez & Michael A. Compagnone & Jesus F. Moreno & Benjamin J. Leslie & Taekjip Ha & Jie Chen, 2021. "Redefining the specificity of phosphoinositide-binding by human PH domain-containing proteins," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24639-y
    DOI: 10.1038/s41467-021-24639-y
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    References listed on IDEAS

    as
    1. Gilbert Di Paolo & Pietro De Camilli, 2006. "Phosphoinositides in cell regulation and membrane dynamics," Nature, Nature, vol. 443(7112), pages 651-657, October.
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