6XW9

Human myelin protein P2 mutant K120S

Summary for 6XW9

• Entry DOI: 10.2210/pdb6xw9/pdb
• Descriptor: Myelin P2 protein, CHLORIDE ION, PALMITIC ACID (3 entities in total)
• Functional Keywords: mutant, peripheral membrane protein, fabp, beta barrel, lipid binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15241.24

Authors

Ruskamo, S.,Lehtimaki, M.,Kursula, P. (deposition date: 2020-01-23, release date: 2020-04-08, Last modification date: 2024-01-24)

Primary citation

Ruskamo, S.,Krokengen, O.C.,Kowal, J.,Nieminen, T.,Lehtimaki, M.,Raasakka, A.,Dandey, V.P.,Vattulainen, I.,Stahlberg, H.,Kursula, P.
Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice.
J.Biol.Chem., 295:8692-8705, 2020

PubMed 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 β-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.

PubMed: 32265298
DOI: 10.1074/jbc.RA120.013087

Experimental method

X-RAY DIFFRACTION (2.9 Å)