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).
Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Carla C
CC
Rospigliosi
Sebastian
S
McClendon
Adrian W
AW
Schmid
Trudy F
TF
Ramlall
Patrick
P
Barré
Hilal A
HA
Lashuel
David
D
Eliezer
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