Charge neutralization and collapse of the C-terminal tail of alpha-synuclein at low pH.
Alpha-synuclein (alphaS) is the primary component of Lewy bodies, the pathological hallmark of Parkinson's Disease. Aggregation of alphaS is thought to proceed from a primarily disordered state with nascent secondary structure through intermediate conformations to oligomeric forms and finally to mature amyloid fibrils. Low pH conditions lead to conformational changes associated with increased alphaS fibril formation. Here we characterize these structural and dynamic changes using solution state NMR measurements of secondary chemical shifts, relaxation parameters, residual dipolar couplings, and paramagnetic relaxation enhancement. We find that the neutralization of negatively charged side-chains eliminates electrostatic repulsion in the C-terminal tail of alphaS and leads to a collapse of this region at low pH. Hydrophobic contacts between the compact C-terminal tail and the NAC (non-amyloid-beta component) region are maintained and may lead to the formation of a globular domain. Transient long-range contacts between the C-terminus of the protein and regions N-terminal to the NAC region are also preserved. Thus, the release of long-range contacts does not play a role in the increased aggregation of alphaS at low pH, which we instead attribute to the increased hydrophobicity of the protein.
McClendon
Sebastian
S
Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Rospigliosi
Carla C
CC
Eliezer
David
D
D000595:Amino Acid Sequence; D004578:Electron Spin Resonance Spectroscopy; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010300:Parkinson Disease / Q000378:metabolism; D055503:Protein Multimerization; D013113:Spin Labels; D055672:Static Electricity; D051844:alpha-Synuclein / Q000737:chemistry*
D013113:Spin Labels; D051844:alpha-Synuclein