Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes

Science Advances
Eiji YamamotoMark S P Sansom

Abstract

Association of peripheral proteins with lipid bilayers regulates membrane signaling and dynamics. Pleckstrin homology (PH) domains bind to phosphatidylinositol phosphate (PIP) molecules in membranes. The effects of local PIP enrichment on the interaction of PH domains with membranes is unclear. Molecular dynamics simulations allow estimation of the binding energy of GRP1 PH domain to PIP3-containing membranes. The free energy of interaction of the PH domain with more than two PIP3 molecules is comparable to experimental values, suggesting that PH domain binding involves local clustering of PIP molecules within membranes. We describe a mechanism of PH binding proceeding via an encounter state to two bound states which differ in the orientation of the protein relative to the membrane, these orientations depending on the local PIP concentration. These results suggest that nanoscale clustering of PIP molecules can control the strength and orientation of PH domain interaction in a concentration-dependent manner.

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Citations

Oct 3, 2020·International Journal of Molecular Sciences·Tania Maffucci, Marco Falasca
Nov 13, 2020·Progress in Lipid Research·Yuanfa YaoYingke Xu
Jan 27, 2021·Advances in Biological Regulation·Forrest Z BowlingMichael V Airola
Feb 28, 2021·Science Advances·Klaas YpermanRoman Pleskot
Apr 2, 2021·Plant Physiology·Femke de Jong, Teun Munnik
May 13, 2021·Molecular Biology of the Cell·Krishnakanth BaratamAnand Srivastava
Jul 22, 2021·Computational and Structural Biotechnology Journal·Jagat RathodWei-Sheng Wu
Aug 8, 2021·International Journal of Molecular Sciences·Nadezhda BarvitenkoAntonella Pantaleo
Sep 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Lukáš SynekMartin Potocký

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