title: Pulsed hydrogen-deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aβ) peptide aggregation.
abstract: Probing the conformational changes of amyloid beta (Aβ) peptide aggregation is challenging owing to the vast heterogeneity of the resulting soluble aggregates. To investigate the formation of these aggregates in solution, we designed an MS-based biophysical approach and applied it to the formation of soluble aggregates of the Aβ42 peptide, the proposed causative agent in Alzheimer's disease. The approach incorporates pulsed hydrogen-deuterium exchange coupled with MS analysis. The combined approach provides evidence for a self-catalyzed aggregation with a lag phase, as observed previously by fluorescence methods. Unlike those approaches, pulsed hydrogen-deuterium exchange does not require modified Aβ42 (e.g., labeling with a fluorophore). Furthermore, the approach reveals that the center region of Aβ42 is first to aggregate, followed by the C and N termini. We also found that the lag phase in the aggregation of soluble species is affected by temperature and Cu(2+) ions. This MS approach has sufficient structural resolution to allow interrogation of Aβ aggregation in physiologically relevant environments. This platform should be generally useful for investigating the aggregation of other amyloid-forming proteins and neurotoxic soluble peptide aggregates.
authors: Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA.
authors: Ying
authors: Y
authors: Zhang
authors: Don L
authors: DL
authors: Rempel
authors: Jun
authors: J
authors: Zhang
authors: Anuj K
authors: AK
authors: Sharma
authors: Liviu M
authors: LM
authors: Mirica
authors: Michael L
authors: ML
authors: Gross
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D015153:Blotting, Western; D003300:Copper / Q000737:chemistry; D003903:Deuterium / Q000378:metabolism; D041961:Deuterium Exchange Measurement / Q000379:methods*; D006801:Humans; D006859:Hydrogen / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods*; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013696:Temperature
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D003300:Copper; D006859:Hydrogen; D003903:Deuterium
keywords: Finke–Watsky mode; amyloid beta peptide; copper; electrospray ionization; soluble Aβ oligomers
references: Nature. 2011 Oct 30;480(7376):268-72
references: 22037310
references: J Am Soc Mass Spectrom. 1998 Mar;9(3):225-33
references: 9879360
references: J Am Chem Soc. 2011 Sep 28;133(38):15008-14
references: 21846101
references: Nat Chem. 2009 Jul;1(4):326-31
references: 20703363
references: J Neurochem. 2009 Sep;110(6):1784-95
references: 19619132
references: Nat Neurosci. 2005 Jan;8(1):79-84
references: 15608634
references: J Neurosci. 2007 Jan 17;27(3):627-33
references: 17234594
references: J Cell Mol Med. 2012 Feb;16(2):287-95
references: 21418518
references: Biochemistry. 2004 Jan 20;43(2):560-8
references: 14717612
references: Neurobiol Dis. 2002 Nov;11(2):330-40
references: 12505425
references: Nat Neurosci. 2001 Sep;4(9):887-93
references: 11528419
references: Protein Sci. 1993 Apr;2(4):522-31
references: 8390883
references: Neuron. 2005 Jul 21;47(2):191-199
references: 16039562
references: Science. 2012 Mar 9;335(6073):1228-31
references: 22403391
references: J Inorg Biochem. 2012 Nov;116:26-36
references: 23010326
references: J Biol Chem. 2002 Aug 30;277(35):32046-53
references: 12058030
references: Chembiochem. 2009 Jan 26;10(2):287-95
references: 19115328
references: Biochemistry. 2011 Nov 1;50(43):9273-82
references: 21899263
references: Biomark Med. 2010 Feb;4(1):51-63
references: 20361010
references: Nature. 2007 May 24;447(7143):453-7
references: 17468747
references: Biochemistry. 2012 Jan 10;51(1):108-17
references: 22129303
references: Biochemistry. 2008 Feb 26;47(8):2413-27
references: 18247636
references: Biochemistry. 2012 May 15;51(19):3957-9
references: 22551351
references: J Cell Mol Med. 2009 Mar;13(3):412-21
references: 19374683
references: J Biol Chem. 2012 Feb 24;287(9):6084-8
references: 22253440
references: J Biol Chem. 2003 Mar 28;278(13):11612-22
references: 12499373
references: Science. 1990 Jun 1;248(4959):1124-6
references: 2111584
references: Biochem Biophys Res Commun. 2002 May 31;294(1):5-10
references: 12054732
references: J Biol Chem. 1998 May 22;273(21):12817-26
references: 9582309
references: Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13597-601
references: 11087832
references: Ann Neurol. 2001 Jun;49(6):697-705
references: 11409420
references: Nature. 1988 Oct 20;335(6192):700-4
references: 2845279
references: Structure. 2010 Oct 13;18(10):1332-41
references: 20947021
references: Nature. 2006 Mar 16;440(7082):352-7
references: 16541076
references: Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14128-33
references: 20660780
references: Expert Rev Proteomics. 2011 Feb;8(1):43-59
references: 21329427
references: J Neurosci. 2011 Dec 7;31(49):18007-12
references: 22159114
references: J Am Chem Soc. 2009 May 13;131(18):6316-7
references: 19385598
references: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17342-7
references: 16293696
references: J Nutr. 2004 May;134(5):1003-6
references: 15113935
references: Biochemistry. 1993 May 11;32(18):4693-7
references: 8490014
references: Mass Spectrom Rev. 2006 Jan-Feb;25(1):158-70
references: 16208684
references: J Am Chem Soc. 2011 Mar 16;133(10):3390-400
references: 21341665
references: J Mass Spectrom. 2012 Dec;47(12):1620-6
references: 23280751
references: Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3321-6
references: 23401512
references: Biochemistry. 2003 Dec 9;42(48):14092-8
references: 14640676
references: J Phys Chem B. 2012 Jun 7;116(22):6311-25
references: 22587454
references: Biochem Biophys Res Commun. 1986 Dec 15;141(2):782-9
references: 3541938
references: J Biol Chem. 2012 Feb 17;287(8):5650-60
references: 22157754
references: J Am Chem Soc. 2010 Mar 31;132(12):4266-80
references: 20218566
references: Methods Enzymol. 1999;309:274-84
references: 10507030
references: J Am Soc Mass Spectrom. 2013 Mar;24(3):450-3
references: 23397137
references: J Am Chem Soc. 2011 May 4;133(17):6505-8
references: 21486030
references: Neurobiol Aging. 2004 May-Jun;25(5):569-80
references: 15172732
references: Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10836-40
references: 8248178
references: Anal Chem. 2011 Jul 1;83(13):5386-93
references: 21635007
references: J Mol Biol. 2007 Jun 15;369(4):909-16
references: 17481654
references: Acc Chem Res. 2010 Aug 17;43(8):1072-9
references: 20557067
references: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10417-22
references: 12925731
references: Biochemistry. 2012 May 1;51(17):3694-703
references: 22486153
references: J Am Chem Soc. 2012 Apr 18;134(15):6625-36
references: 22452395
references: Proc Natl Acad Sci U S A. 2012 May 15;109(20):7717-22
references: 22547798
references: Anal Chem. 2009 Oct 1;81(19):7892-9
references: 19694441
references: Biochemistry. 2005 Jun 21;44(24):8627-33
references: 15952769
references: Anal Chem. 2006 Feb 15;78(4):1005-14
references: 16478090