title: Residue histidine 50 plays a key role in protecting α-synuclein from aggregation at physiological pH.
abstract: α-Synuclein (αSyn) aggregation is involved in the pathogenesis of Parkinson disease (PD). Recently, substitution of histidine 50 in αSyn with a glutamine, H50Q, was identified as a new familial PD mutant. Here, nuclear magnetic resonance (NMR) studies revealed that the H50Q substitution causes an increase of the flexibility of the C-terminal region. This finding provides direct evidence that this PD-causing mutant can mediate long range effects on the sampling of αSyn conformations. In vitro aggregation assays showed that substitution of His-50 with Gln, Asp, or Ala promotes αSyn aggregation, whereas substitution with the positively charged Arg suppresses αSyn aggregation. Histidine carries a partial positive charge at neutral pH, and so our result suggests that positively charged His-50 plays a role in protecting αSyn from aggregation under physiological conditions.
authors.affiliation: From the Department of Biochemistry and Molecular Genetics and.
authors.forename: Ying-Chih
authors.initials: YC
authors.lastname: Chi
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Armstrong
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045 and david.jones@ucdenver.edu.
authors.forename: David N M
authors.initials: DN
authors.lastname: Jones
authors.affiliation: From the Department of Biochemistry and Molecular Genetics and elan.eisenmesser@ucdenver.edu.
authors.forename: Elan Z
authors.initials: EZ
authors.lastname: Eisenmesser
authors.affiliation: From the Department of Biochemistry and Molecular Genetics and changwei.liu@ucdenver.edu.
authors.forename: Chang-Wei
authors.initials: CW
authors.lastname: Liu
mesh_terms: D019943:Amino Acid Substitution / Q000502:physiology; D002021:Buffers; D004563:Electrochemistry; D006639:Histidine / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019906:Nuclear Magnetic Resonance, Biomolecular; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D056811:Unfolded Protein Response / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D002021:Buffers; C497604:SNCA protein, human; D051844:alpha-Synuclein; D006639:Histidine
keywords: Mutant; Nuclear Magnetic Resonance; Parkinson Disease; Protein Aggregation; Synuclein
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