Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice

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Ruskamo , S , Krokengen , O C , Kowal , J , Nieminen , T , Lehtimäki , M , Raasakka , A , Dandey , V P , Vattulainen , I , Stahlberg , H & Kursula , P 2020 , ' Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice ' , Journal of Biological Chemistry , vol. 295 , no. 26 , pp. 8692-8705 . https://doi.org/10.1074/jbc.RA120.013087

Title: Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice
Author: Ruskamo, Salla; Krokengen, Oda C.; Kowal, Julia; Nieminen, Tuomo; Lehtimäki, Mari; Raasakka, Arne; Dandey, Venkata P.; Vattulainen, Ilpo; Stahlberg, Henning; Kursula, Petri
Contributor: University of Helsinki, Department of Physics
Date: 2020-06-26
Language: eng
Number of pages: 14
Belongs to series: Journal of Biological Chemistry
ISSN: 0021-9258
URI: http://hdl.handle.net/10138/325966
Abstract: Myelin protein P2 is a peripheral membrane protein of the fatty acid?binding protein family that functions in the formation and maintenance of the peripheral nerve myelin sheath. Several P2 gene mutations cause human Charcot-Marie-Tooth neuropathy, but the mature myelin sheath assembly mechanism is unclear. Here, cryo-EM of myelin-like proteolipid multilayers revealed an ordered three-dimensional (3D) lattice of P2 molecules between stacked lipid bilayers, visualizing supramolecular assembly at the myelin major dense line. The data disclosed that a single P2 layer is inserted between two bilayers in a tight intermembrane space of ?3 nm, implying direct interactions between P2 and two membrane surfaces. X-ray diffraction from P2-stacked bicelle multilayers revealed lateral protein organization, and surface mutagenesis of P2 coupled with structure-function experiments revealed a role for both the portal region of P2 and its opposite face in membrane interactions. Atomistic molecular dynamics simulations of P2 on model membrane surfaces suggested that Arg-88 is critical for P2-membrane interactions, in addition to the helical lid domain. Negatively charged lipid headgroups stably anchored P2 on the myelin-like bilayer surface. Membrane binding may be accompanied by opening of the P2 ?-barrel structure and ligand exchange with the apposing bilayer. Our results provide an unprecedented view into an ordered, multilayered biomolecular membrane system induced by the presence of a peripheral membrane protein from human myelin. This is an important step toward deciphering the 3D assembly of a mature myelin sheath at the molecular level.
Subject: membrane structure
protein structure
myelin
molecular dynamics
membrane biophysics
membrane protein
membrane bilayer
Charcot-Marie-Tooth disease
neuropathy
proteolipid
ACID-BINDING PROTEIN
PO PROTEIN
PHOSPHOLIPID-MEMBRANES
FATTY-ACIDS
RESOLUTION
CRYSTALLIZATION
LOCALIZATION
P2-PROTEIN
SCATTERING
ADHESION
116 Chemical sciences
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