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J Am Soc Mass Spectrom. 2018 Sep;29(9):1870-1880. doi: 10.1007/s13361-018-2002-2. Epub 2018 Jun 27.

Native Top-Down Mass Spectrometry and Ion Mobility MS for Characterizing the Cobalt and Manganese Metal Binding of α-Synuclein Protein.

Author information

1
Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, CA, 90095, USA.
2
Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
3
Department of Chemistry, Korea University, Seoul, Republic of Korea.
4
Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, CA, 90095, USA. JLoo@chem.ucla.edu.
5
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, UCLA Molecular Biology Institute, and UCLA/DOE Institute for Genomics and Proteomics, University of California-Los Angeles, Los Angeles, CA, 90095, USA. JLoo@chem.ucla.edu.

Abstract

Structural characterization of intrinsically disordered proteins (IDPs) has been a major challenge in the field of protein science due to limited capabilities to obtain full-length high-resolution structures. Native ESI-MS with top-down MS was utilized to obtain structural features of protein-ligand binding for the Parkinson's disease-related protein, α-synuclein (αSyn), which is natively unstructured. Binding of heavy metals has been implicated in the accelerated formation of αSyn aggregation. Using high-resolution Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry, native top-down MS with various fragmentation methods, including electron capture dissociation (ECD), collisional activated dissociation (CAD), and multistage tandem MS (MS3), deduced the binding sites of cobalt and manganese to the C-terminal region of the protein. Ion mobility MS (IM-MS) revealed a collapse toward compacted states of αSyn upon metal binding. The combination of native top-down MS and IM-MS provides structural information of protein-ligand interactions for intrinsically disordered proteins. Graphical Abstract ᅟ.

KEYWORDS:

Electron capture dissociation; Electrospray ionization; Metal binding; Native mass spectrometry; Protein-ligand complex; Top-down mass spectrometry; α-Synuclein

PMID:
29951842
PMCID:
PMC6087494
[Available on 2019-09-01]
DOI:
10.1007/s13361-018-2002-2
[Indexed for MEDLINE]

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