title: Molecular determinants of α-synuclein mutants' oligomerization and membrane interactions.
abstract: Parkinson's disease (PD) is associated with the formation of toxic α-synuclein oligomers that can penetrate the cell membrane. Familial forms of PD are caused by the point mutations A53T, A30P, E46K, and H50Q. Artificial point mutations E35K and E57K also increase oligomerization and pore formation. We generated structural conformations of α-synuclein and the above-mentioned mutants using molecular dynamics. We elucidated four main regions in these conformers contacting the membrane and found that the region including residues 39-45 (Zone2) may have maximum membrane penetration. E57K mutant had the highest rate of interaction with the membrane, followed by A53T, E46K, and E35K mutants and wild type (wt) α-synuclein. The mutant A30P had the smallest percentage of conformers that contact the membrane by Zone 2 than all other mutants and wt α-synuclein. These results were confirmed experimentally in vitro. We identified the key amino acids that can interact with the membrane (Y38, E62, and N65 (first hydrophilic layer); E104, E105, and D115 (second hydrophilic layer), and V15 and V26 (central hydrophobic layer)) and the residues that are involved in the interprotein contacts (L38, V48, V49, Q62, and T64). Understanding the molecular interactions of α-synuclein mutants is important for the design of compounds blocking the formation of toxic oligomers.
authors.affiliation: †San Diego Supercomputer Center, ‡Moores Cancer Center, §Department of Neurosciences, and ∥Department of Pathology, University of California San Diego, La Jolla, California 92093, United States.
authors.forename: Igor F
authors.initials: IF
authors.lastname: Tsigelny
authors.affiliation: †San Diego Supercomputer Center, ‡Moores Cancer Center, §Department of Neurosciences, and ∥Department of Pathology, University of California San Diego, La Jolla, California 92093, United States.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Sharikov
authors.affiliation: †San Diego Supercomputer Center, ‡Moores Cancer Center, §Department of Neurosciences, and ∥Department of Pathology, University of California San Diego, La Jolla, California 92093, United States.
authors.forename: Valentina L
authors.initials: VL
authors.lastname: Kouznetsova
authors.affiliation: †San Diego Supercomputer Center, ‡Moores Cancer Center, §Department of Neurosciences, and ∥Department of Pathology, University of California San Diego, La Jolla, California 92093, United States.
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Greenberg
authors.affiliation: †San Diego Supercomputer Center, ‡Moores Cancer Center, §Department of Neurosciences, and ∥Department of Pathology, University of California San Diego, La Jolla, California 92093, United States.
authors.forename: Wolf
authors.initials: W
authors.lastname: Wrasidlo
authors.affiliation: †San Diego Supercomputer Center, ‡Moores Cancer Center, §Department of Neurosciences, and ∥Department of Pathology, University of California San Diego, La Jolla, California 92093, United States.
authors.forename: Cassia
authors.initials: C
authors.lastname: Overk
authors.affiliation: †San Diego Supercomputer Center, ‡Moores Cancer Center, §Department of Neurosciences, and ∥Department of Pathology, University of California San Diego, La Jolla, California 92093, United States.
authors.forename: Tania
authors.initials: T
authors.lastname: Gonzalez
authors.affiliation: †San Diego Supercomputer Center, ‡Moores Cancer Center, §Department of Neurosciences, and ∥Department of Pathology, University of California San Diego, La Jolla, California 92093, United States.
authors.forename: Margarita
authors.initials: M
authors.lastname: Trejo
authors.affiliation: †San Diego Supercomputer Center, ‡Moores Cancer Center, §Department of Neurosciences, and ∥Department of Pathology, University of California San Diego, La Jolla, California 92093, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.affiliation: †San Diego Supercomputer Center, ‡Moores Cancer Center, §Department of Neurosciences, and ∥Department of Pathology, University of California San Diego, La Jolla, California 92093, United States.
authors.forename: Kori
authors.initials: K
authors.lastname: Kosberg
authors.affiliation: †San Diego Supercomputer Center, ‡Moores Cancer Center, §Department of Neurosciences, and ∥Department of Pathology, University of California San Diego, La Jolla, California 92093, United States.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008958:Models, Molecular; D009447:Neuroblastoma / Q000473:pathology; D017711:Nonlinear Dynamics; D017354:Point Mutation / Q000235:genetics*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D014162:Transfection; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein
keywords: membrane interactions; molecular dynamics; neurodegeneration; oligomers; α-Synuclein; α-synuclein mutants