Modes of Interaction of Pleckstrin Homology Domains with Membranes: Toward a Computational Biochemistry of Membrane Recognition.

Autor: Naughton FB; Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom., Kalli AC; Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom; Leeds Institute of Cancer and Pathology, St James' University Hospital, School of Medicine, University of Leeds, Leeds, United Kingdom., Sansom MSP; Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom. Electronic address: mark.sansom@bioch.ox.ac.uk.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2018 Feb 02; Vol. 430 (3), pp. 372-388. Date of Electronic Publication: 2017 Dec 20.
DOI: 10.1016/j.jmb.2017.12.011
Abstrakt: Pleckstrin homology (PH) domains mediate protein-membrane interactions by binding to phosphatidylinositol phosphate (PIP) molecules. The structural and energetic basis of selective PH-PIP interactions is central to understanding many cellular processes, yet the molecular complexities of the PH-PIP interactions are largely unknown. Molecular dynamics simulations using a coarse-grained model enables estimation of free-energy landscapes for the interactions of 12 different PH domains with membranes containing PIP 2 or PIP 3 , allowing us to obtain a detailed molecular energetic understanding of the complexities of the interactions of the PH domains with PIP molecules in membranes. Distinct binding modes, corresponding to different distributions of cationic residues on the PH domain, were observed, involving PIP interactions at either the "canonical" (C) and/or "alternate" (A) sites. PH domains can be grouped by the relative strength of their C- and A-site interactions, revealing that a higher affinity correlates with increased C-site interactions. These simulations demonstrate that simultaneous binding of multiple PIP molecules by PH domains contributes to high-affinity membrane interactions, informing our understanding of membrane recognition by PH domains in vivo.
(Copyright © 2017. Published by Elsevier Ltd.)
Databáze: MEDLINE
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