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: Igor F Tsigelny, Yuriy Sharikov, Valentina L Kouznetsova, Jerry P Greenberg, Wolf Wrasidlo, Cassia Overk, Tania Gonzalez, Margarita Trejo, Brian Spencer, Kori Kosberg, Eliezer Masliah
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 6 Issue 3 Pg. 403-16 (Mar 18 2015) ISSN: 1948-7193 [Electronic] United States
• PMID: 25561023 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• alpha-Synuclein

Topics

• Animals
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Computer Simulation
• Humans
• Magnetic Resonance Imaging
• Models, Molecular
• Neuroblastoma (pathology)
• Nonlinear Dynamics
• Point Mutation (genetics)
• Protein Conformation
• Protein Structure, Tertiary (genetics)
• Rats
• Transfection
• alpha-Synuclein (chemistry, genetics, metabolism)