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Spermine Binding to Parkinson’s Protein α-Synuclein and Its Disease-Related A30P and A53T Mutants

Grabenauer, Megan and Bernstein, Summer L. and Lee, Jennifer C. and Wyttenbach, Thomas and Dupuis, Nicholas F. and Gray, Harry B. and Winkler, Jay R. and Bowers, Michael T. (2008) Spermine Binding to Parkinson’s Protein α-Synuclein and Its Disease-Related A30P and A53T Mutants. Journal of Physical Chemistry B, 112 (35). pp. 11147-11154. ISSN 1520-6106. PMCID PMC2639767. https://resolver.caltech.edu/CaltechAUTHORS:GRAjpcb08

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Abstract

Aggregation of α-synuclein (α-syn), a protein implicated in Parkinson’s disease (PD), is believed to progress through formation of a partially folded intermediate. Using nanoelectrospray ionization (nano-ESI) mass spectrometry combined with ion mobility measurements we found evidence for a highly compact partially folded family of structures for α-syn and its disease-related A53T mutant with net charges of −6, −7, and −8. For the other early onset PD mutant, A30P, this highly compact population was only evident when the protein had a net charge of −6. When bound to spermine near physiologic pH, all three proteins underwent a charge reduction from the favored solution charge state of −10 to a net charge of −6. This charge reduction is accompanied by a dramatic size reduction of about a factor of 2 (cross section of 2600 Å^2 (−10 charge state) down to 1430 Å^2 (−6 charge state)). We conclude that spermine increases the aggregation rate of α-syn by inducing a collapsed conformation, which then proceeds to form aggregates.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/jp801175wDOIArticle
http://pubs.acs.org/doi/abs/10.1021/jp801175wPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639767PubMed CentralArticle
ORCID:
AuthorORCID
Winkler, Jay R.0000-0002-4453-9716
Contact Email Address:bowers@chem.ucsb.edu
Additional Information:Copyright © 2008 American Chemical Society. Received: February 8, 2008; Revised Manuscript Received: June 11, 2008. Web Release Date: August 9, 2008. We thank Professor Joe Loo for suggesting the experiments with spermine and Dr. Catherine J. Carpenter for help with preparation of the figures. Support from the National Science Foundation (grant CHE-0503728 (M.T.B.)), National Institutes of Health (grant GM068461 (J.R.W.)), the Ellison Medical Foundation (Senior Scholar Award in Aging to H.B.G.), and the Arnold and Mabel Beckman Foundation (J.C.L.) are gratefully acknowledged.
Funders:
Funding AgencyGrant Number
NSFCHE-0503728
NIHGM068461
Ellison Medical FoundationUNSPECIFIED
Arnold and Mabel Beckman FoundationUNSPECIFIED
Issue or Number:35
PubMed Central ID:PMC2639767
Record Number:CaltechAUTHORS:GRAjpcb08
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:GRAjpcb08
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11731
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:22 Sep 2008 15:59
Last Modified:03 Oct 2019 00:21

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