Residue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH |
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Authors: | Ying-Chih Chi Geoffrey S Armstrong David N M Jones Elan Z Eisenmesser Chang-Wei Liu |
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Institution: | From the ‡Department of Biochemistry and Molecular Genetics and ;¶Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045 and ;§Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309 |
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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. |
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Keywords: | Mutant Nuclear Magnetic Resonance Parkinson Disease Protein Aggregation Synuclein |
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