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Systematic simulation of the interactions of Pleckstrin homology domains with membranes

Kyle I.P. Le Huray, He Wang, Frank Sobott, Antreas C. Kalli
doi: https://doi.org/10.1101/2021.12.16.472954
Kyle I.P. Le Huray
1School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
2Astbury Centre for Structural and Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
3Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, UK
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He Wang
4School of Computing, University of Leeds, Leeds, UK
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Frank Sobott
1School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
2Astbury Centre for Structural and Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
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Antreas C. Kalli
2Astbury Centre for Structural and Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
3Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, UK
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Abstract

Pleckstrin homology (PH) domains can recruit proteins to membranes by recognition of phosphatidylinositol phosphates (PIPs). Here we report the systematic simulation of the interactions of 100 mammalian PH domains with PIP containing model membranes. Comparison with crystal structures of PH domains bound to PIP analogues demonstrates that our method correctly identifies interactions at known canonical and non-canonical sites, while revealing additional functionally important sites for interaction not observed in the crystal structure, such as for P-Rex1 and Akt1. At the family level, we find that the β1 and β2 strands and their connecting loop constitute the primary PIP interaction site for the majority of PH domains, but we highlight interesting exceptional cases. Simultaneous interaction with multiple PIPs and clustering of PIPs induced by PH domain binding are also observed. Our findings support a general paradigm for PH domain membrane association involving multivalent interactions with anionic lipids.

Teaser Simulating the binding of 100 Pleckstrin homology domains to cell membranes reveals patterns in their lipid interactions.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* a.kalli{at}leeds.ac.uk

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 16, 2021.
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Systematic simulation of the interactions of Pleckstrin homology domains with membranes
Kyle I.P. Le Huray, He Wang, Frank Sobott, Antreas C. Kalli
bioRxiv 2021.12.16.472954; doi: https://doi.org/10.1101/2021.12.16.472954
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Systematic simulation of the interactions of Pleckstrin homology domains with membranes
Kyle I.P. Le Huray, He Wang, Frank Sobott, Antreas C. Kalli
bioRxiv 2021.12.16.472954; doi: https://doi.org/10.1101/2021.12.16.472954

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