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Membrane Binding and Self-Association of the Epsin N-Terminal Homology Domain
Authors:Chun-Liang Lai  Christine C Jao  Edward LymanJennifer L Gallop  Brian J PeterHarvey T McMahon  Ralf Langen  Gregory A Voth
Institution:
  • 1 Department of Chemistry, Institute of Biophysical Dynamics, James Franck Institute, and Computation Institute, University of Chicago, 5735S Ellis Avenue, Chicago, IL 60637, USA
  • 2 Zilkha Neurogenetic Institute, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA
  • 3 Department of Physics and Astrophysics, and Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
  • 4 MRC Laboratory of Molecular Biology, University of Cambridge, Hills Road, Cambridge CB2 2QH, UK
  • Abstract:Epsin possesses a conserved epsin N-terminal homology (ENTH) domain that acts as a phosphatidylinositol 4,5-bisphosphate‐lipid‐targeting and membrane‐curvature‐generating element. Upon binding phosphatidylinositol 4,5‐bisphosphate, the N-terminal helix (H0) of the ENTH domain becomes structured and aids in the aggregation of ENTH domains, which results in extensive membrane remodeling. In this article, atomistic and coarse-grained (CG) molecular dynamics (MD) simulations are used to investigate the structure and the stability of ENTH domain aggregates on lipid bilayers. EPR experiments are also reported for systems composed of different ENTH-bound membrane morphologies, including membrane vesicles as well as preformed membrane tubules. The EPR data are used to help develop a molecular model of ENTH domain aggregates on preformed lipid tubules that are then studied by CG MD simulation. The combined computational and experimental approach suggests that ENTH domains exist predominantly as monomers on vesiculated structures, while ENTH domains self-associate into dimeric structures and even higher‐order oligomers on the membrane tubes. The results emphasize that the arrangement of ENTH domain aggregates depends strongly on whether the local membrane curvature is isotropic or anisotropic. The molecular mechanism of ENTH‐domain-induced membrane vesiculation and tubulation and the implications of the epsin's role in clathrin-mediated endocytosis resulting from the interplay between ENTH domain membrane binding and ENTH domain self-association are also discussed.
    Keywords:ENTH  epsin N-terminal homology  PIP2  phosphatidylinositol 4  5-bisphosphate  CG  coarse-grained  MD  molecular dynamics  CME  clathrin-mediated endocytosis  N-BAR  N-terminal Bin/Amphiphysin/Rvs-homology  EM  electron microscopy  HAS  hybrid analytical systematic  PMF  potential of mean force  RT  room temperature
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