title: Polymorphism of Alzheimer's Abeta17-42 (p3) oligomers: the importance of the turn location and its conformation.
abstract: Abeta(17-42) (so-called p3) amyloid is detected in vivo in the brains of individuals with Alzheimer's disease or Down's syndrome. We investigated the polymorphism of Abeta(17-42) oligomers based on experimental data from steady-state NMR measurements, electron microscopy, two-dimensional hydrogen exchange, and mutational studies, using all-atom molecular-dynamics simulation with explicit solvent. We assessed the structural stability and the populations. Our results suggest that conformational differences in the U-turn of Abeta(17-42) lead to polymorphism in beta-sheet registration and retention of an ordered beta-strand organization at the termini. Further, although the parallel Abeta(17-42) oligomer organization is the most stable of the conformers investigated here, different antiparallel Abeta(17-42) organizations are also stable and compete with the parallel architectures, presenting a polymorphic population. In this study we propose that 1), the U-turn conformation is the primary factor leading to polymorphism in the assembly of Abeta(17-42) oligomers, and is also coupled to oligomer growth; and 2), both parallel Abeta(17-42) oligomers and an assembly of Abeta(17-42) oligomers that includes both parallel and antiparallel organizations contribute to amyloid fibril formation. Finally, since a U-turn motif generally appears in amyloids formed by full proteins or long fragments, and since to date these have been shown to exist only in parallel architectures, our results apply to a broad range of oligomers and fibrils.
authors.affiliation: Center for Cancer Research Nanobiology Program, National Cancer Institute-Frederick, Frederick, Maryland, USA.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Miller
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure*; D003198:Computer Simulation; D008956:Models, Chemical; D008957:Models, Genetic; D008958:Models, Molecular; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011487:Protein Conformation
chemical_list: D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D010446:Peptide Fragments; C086839:amyloid beta-protein (17-42)
references.citation: Nature. 2004 Mar 18;428(6980):319-23
references.pmid: 15029195
references.citation: Curr Opin Chem Biol. 2006 Oct;10(5):445-52
references.pmid: 16935548
references.citation: Clin Biochem. 1993 Oct;26(5):339-49
references.pmid: 8299204
references.citation: Genetics. 1996 Dec;144(4):1375-86
references.pmid: 8978027
references.citation: EMBO J. 2005 Sep 7;24(17):3082-92
references.pmid: 16096644
references.citation: Chem Biol. 1997 Dec;4(12):951-9
references.pmid: 9427660
references.citation: Nat Neurosci. 2005 Jan;8(1):79-84
references.pmid: 15608634
references.citation: Cell. 2005 Apr 8;121(1):49-62
references.pmid: 15820678
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9196-201
references.pmid: 12093917
references.citation: Annu Rev Cell Biol. 1994;10:373-403
references.pmid: 7888181
references.citation: Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9513-7
references.pmid: 8415732
references.citation: J Biol Chem. 1995 Oct 13;270(41):23895-8
references.pmid: 7592576
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16392-9
references.pmid: 12149514
references.citation: Biophys J. 2000 Dec;79(6):3282-93
references.pmid: 11106631
references.citation: Neurobiol Aging. 1994 Mar-Apr;15(2):143-52
references.pmid: 7838284
references.citation: J Struct Biol. 1997 Jun;119(1):17-27
references.pmid: 9216085
references.citation: Biochim Biophys Acta. 2004 May 6;1698(2):131-53
references.pmid: 15134647
references.citation: Biophys J. 2006 May 15;90(10):3365-74
references.pmid: 16500972
references.citation: Angew Chem Int Ed Engl. 2008;47(31):5842-5
references.pmid: 18528917
references.citation: FEBS Lett. 2008 Jun 11;582(13):1865-70
references.pmid: 18474239
references.citation: J Neurochem. 1995 Oct;65(4):1431-44
references.pmid: 7561836
references.citation: Biophys J. 2006 Jun 15;90(12):4618-29
references.pmid: 16565054
references.citation: J Biol Chem. 2003 Sep 12;278(37):35317-24
references.pmid: 12840025
references.citation: J Neurosci Res. 2002 Sep 1;69(5):567-77
references.pmid: 12210822
references.citation: Neuron. 2004 Sep 30;44(1):181-93
references.pmid: 15450169
references.citation: Annu Rev Cell Dev Biol. 2002;18:25-51
references.pmid: 12142279
references.citation: Biophys J. 2009 Jan;96(2):442-52
references.pmid: 19167295
references.citation: Annu Rev Neurosci. 2003;26:267-98
references.pmid: 12704221
references.citation: J Phys Chem B. 1998 Apr 30;102(18):3586-616
references.pmid: 24889800
references.citation: J Mol Biol. 2009 Feb 27;386(3):869-77
references.pmid: 19038266
references.citation: J Neuropathol Exp Neurol. 1997 Apr;56(4):321-39
references.pmid: 9100663
references.citation: J Biol Chem. 1996 Dec 27;271(52):33623-31
references.pmid: 8969231
references.citation: Biophys J. 2007 Nov 1;93(9):3046-57
references.pmid: 17675353
references.citation: Biophys J. 2007 May 1;92(9):3032-9
references.pmid: 17293399
references.citation: Curr Alzheimer Res. 2008 Jun;5(3):244-50
references.pmid: 18537541
references.citation: J Am Chem Soc. 2006 Dec 20;128(50):16159-68
references.pmid: 17165769
references.citation: Nature. 2003 Dec 18;426(6968):884-90
references.pmid: 14685248
references.citation: Biomed Pharmacother. 1994;48(7):312-8
references.pmid: 7858162
references.citation: J Struct Biol. 1995 Jul-Aug;115(1):1-15
references.pmid: 7577226
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17342-7
references.pmid: 16293696
references.citation: Am J Pathol. 1996 Aug;149(2):585-96
references.pmid: 8701997
references.citation: Biochemistry. 2006 Jan 17;45(2):498-512
references.pmid: 16401079
references.citation: J Mol Biol. 2001 Apr 13;307(5):1247-60
references.pmid: 11292339
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14126-31
references.pmid: 12391326
references.citation: Structure. 2006 Jun;14(6):1059-72
references.pmid: 16765899
references.citation: J Mol Biol. 2005 Sep 30;352(4):952-60
references.pmid: 16126222
references.citation: Annu Rev Biochem. 1992;61:947-75
references.pmid: 1497327
references.citation: J Mol Biol. 2004 Jan 2;335(1):247-60
references.pmid: 14659754
references.citation: Curr Opin Struct Biol. 2000 Feb;10(1):60-8
references.pmid: 10679462
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13175-9
references.pmid: 10557293
references.citation: Brain. 2002 Sep;125(Pt 9):2036-43
references.pmid: 12183349
references.citation: J Comput Chem. 2003 Aug;24(11):1348-56
references.pmid: 12827676
references.citation: J Struct Biol. 2005 Feb;149(2):213-8
references.pmid: 15681237
references.citation: Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):571-6
references.pmid: 10639120
references.citation: Science. 2003 Apr 18;300(5618):486-9
references.pmid: 12702875
references.citation: J Phys Chem B. 2008 Jun 5;112(22):6856-65
references.pmid: 18457440
references.citation: Nature. 2004 Mar 18;428(6980):323-8
references.pmid: 15029196
references.citation: J Biol Chem. 2004 Apr 9;279(15):14999-5013
references.pmid: 14736893
references.citation: Nature. 2002 Apr 4;416(6880):507-11
references.pmid: 11932737
references.citation: J Biol Chem. 2005 Apr 29;280(17):17294-300
references.pmid: 15722360
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2817-22
references.pmid: 14981241
references.citation: Biochemistry. 2000 Nov 14;39(45):13748-59
references.pmid: 11076514
references.citation: J Mol Biol. 2001 Jun 29;310(1):157-68
references.pmid: 11419943
references.citation: Q Rev Biophys. 1998 Feb;31(1):1-39
references.pmid: 9717197
references.citation: Protein Pept Lett. 2004 Jun;11(3):213-28
references.pmid: 15182223
references.citation: Protein Sci. 2006 Jun;15(6):1239-47
references.pmid: 16731963
references.citation: Nat Cell Biol. 2004 Nov;6(11):1054-61
references.pmid: 15516999
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18349-54
references.pmid: 19015532
references.citation: Adv Protein Chem. 2006;73:125-80
references.pmid: 17190613
references.citation: J Biol Chem. 2005 Feb 25;280(8):6269-75
references.pmid: 15576361
references.citation: Curr Opin Struct Biol. 2003 Apr;13(2):146-59
references.pmid: 12727507
references.citation: Science. 2005 Jan 14;307(5707):262-5
references.pmid: 15653506
references.citation: Acc Chem Res. 2005 Nov;38(11):885-91
references.pmid: 16285711
references.citation: J Mol Biol. 2007 Feb 9;366(1):275-85
references.pmid: 17166516
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17753-8
references.pmid: 17093048
references.citation: Nature. 2004 Aug 5;430(7000):631-9
references.pmid: 15295589
references.citation: J Am Chem Soc. 2008 Nov 12;130(45):14990-5001
references.pmid: 18937465
references.citation: J Mol Biol. 2005 Nov 4;353(4):804-21
references.pmid: 16213524