E46K Parkinson's-linked mutation enhances C-terminal-to-N-terminal contacts in alpha-synuclein.
Parkinson's disease (PD) is associated with the deposition of fibrillar aggregates of the protein alpha-synuclein (alphaS) in neurons. Intramolecular contacts between the acidic C-terminal tail of alphaS and its N-terminal region have been proposed to regulate alphaS aggregation, and two originally described PD mutations, A30P and A53T, reportedly reduce such contacts. We find that the most recently discovered PD-linked alphaS mutation E46K, which also accelerates the aggregation of the protein, does not interfere with C-terminal-to-N-terminal contacts and instead enhances such contacts. Furthermore, we do not observe a substantial reduction in such contacts in the two previously characterized mutants. Our results suggest that C-terminal-to-N-terminal contacts in alphaS are not strongly protective against aggregation, and that the dominant mechanism by which PD-linked mutations facilitate alphaS aggregation may be altering the physicochemical properties of the protein such as net charge (E46K) and secondary structure propensity (A30P and A53T).
Rospigliosi
Carla C
CC
Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College, New York, NY 10065, USA.
McClendon
Sebastian
S
Schmid
Adrian W
AW
Ramlall
Trudy F
TF
Barré
Patrick
P
Lashuel
Hilal A
HA
Eliezer
David
D
D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010300:Parkinson Disease / Q000235:genetics*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary / Q000235:genetics*; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
D010446:Peptide Fragments; D051844:alpha-Synuclein