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 and their penetration 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 abovementioned mutants using molecular dynamics. We elucidated four main regions in these conformers contacting the membrane and found that the region including residues 37–45 (Zone2) may have maximum membrane penetration. E57K mutant had the highest rate of interaction with the membrane by Zone2, followed by A53T, E46K, E35K mutants, and wt α-synuclein. The mutant A30P had the smallest percentage of conformers that contact the membrane than all other mutants and wt α-synuclein. These results were confirmed by experiments. We identified the key amino acids that can interact with the membrane (Y38, E62, and N65 (1st hydrophilic layer); E104, E105, and D115 (2nd 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.

Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

“…A comparative sequence and structural analysis suggested that the 32-58 region of SYN is critical for the stability and the secondary structure of the protein [43]. This is consistent with another study, in which predominantly the 39-45 aa segment, among others, was proposed to be involved in the membrane penetration [44]. The increased oligomerization efficacy of SYN mutants is associated with enhanced propensity to penetrate the membrane [45].…”

Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies

“…Indeed, whereas A53T and H50Q exhibit a higher propensity to interact with membranes (Tsigelny et al . ), A30P, G51D and A53E attenuate this propensity (Jo et al . ; Fares et al .…”

α-synuclein dimer structures found from computational simulations

“…This region also contains several residues (A30, E46, H50 G51 and A53) whose mutations (A30P, E46K, H50Q, G51D, A53T) alter the aggregation process [16][17][18][19][20][21][22][23] and are linked to familial forms of Parkinson's disease [24,25]. The central region, consisting of residues 61-95, is highly hydrophobic [26,27].…”