Polymorphism of Alzheimer's Abeta17-42 (p3) oligomers: the importance of the turn location and its conformation.
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.
Miller
Yifat
Y
Center for Cancer Research Nanobiology Program, National Cancer Institute-Frederick, Frederick, Maryland, USA.
Ma
Buyong
B
Nussinov
Ruth
R
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
D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D010446:Peptide Fragments; C086839:amyloid beta-protein (17-42)
Nature. 2004 Mar 18;428(6980):319-23
15029195
Curr Opin Chem Biol. 2006 Oct;10(5):445-52
16935548
Clin Biochem. 1993 Oct;26(5):339-49
8299204
Genetics. 1996 Dec;144(4):1375-86
8978027
EMBO J. 2005 Sep 7;24(17):3082-92
16096644
Chem Biol. 1997 Dec;4(12):951-9
9427660
Nat Neurosci. 2005 Jan;8(1):79-84
15608634
Cell. 2005 Apr 8;121(1):49-62
15820678
Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9196-201
12093917
Annu Rev Cell Biol. 1994;10:373-403
7888181
Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9513-7
8415732
J Biol Chem. 1995 Oct 13;270(41):23895-8
7592576
Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16392-9
12149514
Biophys J. 2000 Dec;79(6):3282-93
11106631
Neurobiol Aging. 1994 Mar-Apr;15(2):143-52
7838284
J Struct Biol. 1997 Jun;119(1):17-27
9216085
Biochim Biophys Acta. 2004 May 6;1698(2):131-53
15134647
Biophys J. 2006 May 15;90(10):3365-74
16500972
Angew Chem Int Ed Engl. 2008;47(31):5842-5
18528917
FEBS Lett. 2008 Jun 11;582(13):1865-70
18474239
J Neurochem. 1995 Oct;65(4):1431-44
7561836
Biophys J. 2006 Jun 15;90(12):4618-29
16565054
J Biol Chem. 2003 Sep 12;278(37):35317-24
12840025
J Neurosci Res. 2002 Sep 1;69(5):567-77
12210822
Neuron. 2004 Sep 30;44(1):181-93
15450169
Annu Rev Cell Dev Biol. 2002;18:25-51
12142279
Biophys J. 2009 Jan;96(2):442-52
19167295
Annu Rev Neurosci. 2003;26:267-98
12704221
J Phys Chem B. 1998 Apr 30;102(18):3586-616
24889800
J Mol Biol. 2009 Feb 27;386(3):869-77
19038266
J Neuropathol Exp Neurol. 1997 Apr;56(4):321-39
9100663
J Biol Chem. 1996 Dec 27;271(52):33623-31
8969231
Biophys J. 2007 Nov 1;93(9):3046-57
17675353
Biophys J. 2007 May 1;92(9):3032-9
17293399
Curr Alzheimer Res. 2008 Jun;5(3):244-50
18537541
J Am Chem Soc. 2006 Dec 20;128(50):16159-68
17165769
Nature. 2003 Dec 18;426(6968):884-90
14685248
Biomed Pharmacother. 1994;48(7):312-8
7858162
J Struct Biol. 1995 Jul-Aug;115(1):1-15
7577226
Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17342-7
16293696
Am J Pathol. 1996 Aug;149(2):585-96
8701997
Biochemistry. 2006 Jan 17;45(2):498-512
16401079
J Mol Biol. 2001 Apr 13;307(5):1247-60
11292339
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14126-31
12391326
Structure. 2006 Jun;14(6):1059-72
16765899
J Mol Biol. 2005 Sep 30;352(4):952-60
16126222
Annu Rev Biochem. 1992;61:947-75
1497327
J Mol Biol. 2004 Jan 2;335(1):247-60
14659754
Curr Opin Struct Biol. 2000 Feb;10(1):60-8
10679462
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13175-9
10557293
Brain. 2002 Sep;125(Pt 9):2036-43
12183349
J Comput Chem. 2003 Aug;24(11):1348-56
12827676
J Struct Biol. 2005 Feb;149(2):213-8
15681237
Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):571-6
10639120
Science. 2003 Apr 18;300(5618):486-9
12702875
J Phys Chem B. 2008 Jun 5;112(22):6856-65
18457440
Nature. 2004 Mar 18;428(6980):323-8
15029196
J Biol Chem. 2004 Apr 9;279(15):14999-5013
14736893
Nature. 2002 Apr 4;416(6880):507-11
11932737
J Biol Chem. 2005 Apr 29;280(17):17294-300
15722360
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2817-22
14981241
Biochemistry. 2000 Nov 14;39(45):13748-59
11076514
J Mol Biol. 2001 Jun 29;310(1):157-68
11419943
Q Rev Biophys. 1998 Feb;31(1):1-39
9717197
Protein Pept Lett. 2004 Jun;11(3):213-28
15182223
Protein Sci. 2006 Jun;15(6):1239-47
16731963
Nat Cell Biol. 2004 Nov;6(11):1054-61
15516999
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18349-54
19015532
Adv Protein Chem. 2006;73:125-80
17190613
J Biol Chem. 2005 Feb 25;280(8):6269-75
15576361
Curr Opin Struct Biol. 2003 Apr;13(2):146-59
12727507
Science. 2005 Jan 14;307(5707):262-5
15653506
Acc Chem Res. 2005 Nov;38(11):885-91
16285711
J Mol Biol. 2007 Feb 9;366(1):275-85
17166516
Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17753-8
17093048
Nature. 2004 Aug 5;430(7000):631-9
15295589
J Am Chem Soc. 2008 Nov 12;130(45):14990-5001
18937465
J Mol Biol. 2005 Nov 4;353(4):804-21
16213524