title: A new structural model of Alzheimer's Aβ42 fibrils based on electron paramagnetic resonance data and Rosetta modeling.
abstract: Brain deposition of Aβ in the form of amyloid plaques is a pathological hallmark of Alzheimer's disease. There are two major species of Aβ in the brain: Aβ42 and Aβ40. Although Aβ40 is several-fold more abundant than Aβ42 in soluble form, Aβ42 is the major component of amyloid plaques. Structural knowledge of Aβ42 fibrils is important both for understanding the process of Aβ aggregation and for designing fibril-targeting drugs. Here we report site-specific structural information of Aβ42 fibrils at 22 residue positions based on electron paramagnetic resonance data. In combination with structure prediction program Rosetta, we modeled Aβ42 fibril structure at atomic resolution. Our Aβ42 fibril model consists of four parallel in-register β-sheets: βN (residues ∼7-13), β1 (residues ∼17-20), β2 (residues ∼32-36), and βC (residues 39-41). The region of β1-loop-β2 in Aβ42 fibrils adopts similar structure as that in Aβ40 fibrils. This is consistent with our cross seeding data that Aβ42 fibril seeds shortened the lag phase of Aβ40 fibrillization. On the other hand, Aβ42 fibrils contain a C-terminal β-arc-β motif with a special turn, termed "arc", at residues 37-38, which is absent in Aβ40 fibrils. Our results can explain both the higher aggregation propensity of Aβ42 and the importance of Aβ42 to Aβ40 ratio in the pathogenesis of Alzheimer's disease.
authors.affiliation: Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Tran
authors.affiliation: Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA. Electronic address: zhefeng@ucla.edu.
authors.forename: Zhefeng
authors.initials: Z
authors.lastname: Guo
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D017434:Protein Structure, Tertiary
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer disease; Amyloid; Aβ; Protein aggregation; Spin labeling
references.citation: Ann Neurol. 1995 Mar;37(3):294-9
references.pmid: 7695229
references.citation: Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):11858-63
references.pmid: 26351699
references.citation: Am J Pathol. 1996 Jan;148(1):259-65
references.pmid: 8546214
references.citation: J Biol Chem. 2004 Dec 10;279(50):52781-8
references.pmid: 15459202
references.citation: Neuron. 2005 Jul 21;47(2):191-9
references.pmid: 16039562
references.citation: Bioorg Med Chem. 2005 Dec 15;13(24):6803-9
references.pmid: 16182533
references.citation: Methods Enzymol. 2005;398:540-54
references.pmid: 16275357
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17342-7
references.pmid: 16293696
references.citation: Biochemistry. 2006 Jan 17;45(2):498-512
references.pmid: 16401079
references.citation: Biochemistry. 2001 Apr 3;40(13):3828-46
references.pmid: 11300763
references.citation: J Biol Chem. 2002 Oct 25;277(43):40810-5
references.pmid: 12181315
references.citation: Biochemistry. 2002 Dec 24;41(51):15436-50
references.pmid: 12484785
references.citation: Science. 2003 Nov 21;302(5649):1364-8
references.pmid: 14631033
references.citation: Arch Biochem Biophys. 1993 Feb 15;301(1):41-52
references.pmid: 8442665
references.citation: Neuron. 1994 Jul;13(1):45-53
references.pmid: 8043280
references.citation: Brain Res. 1994 Dec 19;667(1):138-42
references.pmid: 7895077
references.citation: J Biol Chem. 2006 Jan 6;281(1):477-83
references.pmid: 16215229
references.citation: Biochemistry. 2006 May 2;45(17):5503-16
references.pmid: 16634632
references.citation: J Mol Biol. 2006 May 12;358(4):1094-105
references.pmid: 16580019
references.citation: Q Rev Biophys. 2006 Feb;39(1):1-55
references.pmid: 16772049
references.citation: J Mol Biol. 2007 Jun 15;369(4):909-16
references.pmid: 17481654
references.citation: Biochem Biophys Res Commun. 2007 Aug 3;359(3):801-5
references.pmid: 17560941
references.citation: J Biol Chem. 2007 Aug 24;282(34):24970-9
references.pmid: 17573347
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17656-61
references.pmid: 17978193
references.citation: Bioorg Med Chem Lett. 2008 Jun 1;18(11):3206-10
references.pmid: 18468894
references.citation: J Biol Chem. 2008 Oct 17;283(42):28176-89
references.pmid: 18694930
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18349-54
references.pmid: 19015532
references.citation: Q Rev Biophys. 2008 Aug-Nov;41(3-4):265-97
references.pmid: 19079806
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4653-8
references.pmid: 19264960
references.citation: FASEB J. 2010 May;24(5):1311-9
references.pmid: 20032312
references.citation: Nat Struct Mol Biol. 2010 May;17(5):561-7
references.pmid: 20383142
references.citation: EMBO J. 2010 Oct 6;29(19):3408-20
references.pmid: 20818335
references.citation: Methods Enzymol. 2011;487:545-74
references.pmid: 21187238
references.citation: J Biol Chem. 2011 Aug 26;286(34):29691-9
references.pmid: 21730048
references.citation: J Biol Chem. 2011 Sep 30;286(39):34244-53
references.pmid: 21832091
references.citation: J Am Chem Soc. 2011 Oct 12;133(40):16013-22
references.pmid: 21882806
references.citation: Biochem Biophys Res Commun. 2011 Oct 28;414(3):512-6
references.pmid: 21986527
references.citation: J Biol Chem. 2012 Feb 17;287(8):5650-60
references.pmid: 22157754
references.citation: Biochem J. 2012 Oct 1;447(1):43-50
references.pmid: 22823461
references.citation: J Struct Biol. 2012 Nov;180(2):374-81
references.pmid: 22967940
references.citation: J Biol Chem. 2013 Jun 28;288(26):18673-83
references.pmid: 23687299
references.citation: J Neurochem. 2013 Aug;126(3):305-11
references.pmid: 23406382
references.citation: Dement Geriatr Cogn Disord. 2013;36(1-2):99-110
references.pmid: 23860354
references.citation: Cell. 2013 Sep 12;154(6):1257-68
references.pmid: 24034249
references.citation: J Biol Chem. 2014 Sep 26;289(39):27300-13
references.pmid: 25118290
references.citation: Nat Struct Mol Biol. 2015 Jun;22(6):499-505
references.pmid: 25938662
references.citation: J Am Chem Soc. 2015 Jun 17;137(23):7509-18
references.pmid: 26001057
references.citation: J Biol Chem. 1995 Mar 31;270(13):7013-6
references.pmid: 7706234