Advances in ion mobility spectrometry-mass spectrometry reveal key insights into amyloid assembly

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BBAPAP-38919; No. of pages: 12; 4C: 2, 3, 4, 6, 7, 8, 9
Biochimica et Biophysica Acta xxx (2012) xxx–xxx

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Advances in ion mobility spectrometry–mass spectrometry reveal key insights into amyloid assembly☆
L.A. Woods, S.E. Radford ⁎, A.E. Ashcroft⁎⁎
Astbury Centre for Structural Molecular Biology & School of Molecular and Cellular Biology, University of Leeds, LS2 9JT, UK

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a b s t r a c t
Interfacing ion mobility spectrometry to mass spectrometry (IMS–MS) has enabled mass spectrometric analyses to extend into an extra dimension, providing unrivalled separation and structural characterization of lowly populatedspecies in heterogeneous mixtures. One biological system that has benefitted significantly from such advances is that of amyloid formation. Using IMS–MS, progress has been made into identifying transiently populated monomeric and oligomeric species for a number of different amyloid systems and has led to an enhanced understanding of the mechanism by which small molecules modulate amyloid formation.This review highlights recent advances in this field, which have been accelerated by the commercial availability of IMS–MS instruments. This article is part of a Special Issue entitled: Mass spectrometry in structural biology. © 2012 Elsevier B.V. All rights reserved.

Article history: Received 30 July 2012 Received in revised form 27 September 2012 Accepted 2 October 2012 Available online xxxxKeywords: Amyloid Ion mobility spectrometry Mass spectrometry Oligomer Ligand binding

1. Introduction Mass spectrometry (MS) has become widely accepted as a tool to analyse biological systems over the past twenty years, subsequent to the pioneering development of electrospray ionization (ESI) [1,2]. The advent of ESI, and other soft ionization techniques such as matrix assisted laser desorptionionization (MALDI) [3], initiated a new field in which a wealth of information about protein structure and macromolecular assemblies can be deduced using MS, including revealing insights about protein/ligand binding and dynamic structure. Whereas the first ESI–MS experiments of biological macromolecules provided accurate molecular mass measurements [2], the technique evolved rapidly such thatstructural information about proteins and their biomolecular complexes could be obtained, in addition to information about protein stability, dynamics and post-translational modifications [4–12]. The use of ESI–MS in structural biology has been accelerated most recently through the coupling of ion mobility spectrometry (IMS) to MS [13–16]. This approach has enabled the detailed analysis of biologicalsystems, particularly in cases where alternative techniques such as crystallography or nuclear magnetic resonance are unable to be

used due to the analyte's poor solubility, large mass, and/or the inability to crystallize, or in cases where the species of interest are present within a heterogeneous mixture [17]. In this review, we describe the principles of mass spectrometry coupled with ionmobility spectrometry (IMS– MS) and discuss how this approach has enhanced our understanding of protein oligomerization during self-assembly into amyloid.

2. Background to ESI–IMS–MS development and application to biological systems Ion mobility spectrometry (IMS) is able to separate complex mixtures of ions based on their shape and/or charge [18,19], yielding structural information complementary tomolecular mass measurements. The technique of IMS relies on separating gaseous ions according to their mobility through a drift-tube filled with a buffer gas [18]. Ions are accelerated through the drift tube by an electric field, wherein ions of differing shapes have different mobilities depending on an ion's characteristic collision cross-section (CCS). Larger, extended ions will experience...
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