Zinc ions promote Alzheimer Abeta aggregation via population shift of polymorphic states.
Although a key factor in Alzheimer's disease etiology is enrichment of Zn(2+) in aggregates, and there are data suggesting that zinc promotes aggregation, how Zn(2+)-Abeta coordination promotes aggregation is elusive. Here we probe the structures and mechanisms through which Zn(2+) can affect amyloidosis. By covalently linking fragments (that have experiment-based coordinates) we observed that, in oligomeric Zn(2+)-Abeta(42), Zn(2+) can simultaneously coordinate intra- and intermolecularly, bridging two peptides. Zinc coordination significantly decreases the solvation energy for large Zn(2+)-Abeta(42) oligomers and thus enhances their aggregation tendency. Zn(2+) binding does not change the beta-sheet association around the C-terminal hydrophobic region; however, it shifts the relative population of the preexisting amyloid polymorphic ensembles. As a result, although a parallel beta-sheet arrangement is still preferred, antiparallel and other less structured assemblies are stabilized, also becoming major species. Overall, Zn(2+) coordination promotes Abeta(42) aggregation leading to less uniform structures. Our replica exchange molecular dynamics simulations further reproduced an experimental observation that the increasing Zn(2+) concentration could slow down the aggregation rate, even though the aggregation rates are still much higher than in Zn(2+)-free solution.
Miller
Yifat
Y
Center for Cancer Research Nanobiology Program, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Ma
Buyong
B
Nussinov
Ruth
R
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002413:Cations, Divalent / Q000737:chemistry; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D012995:Solubility; D015032:Zinc / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D002413:Cations, Divalent; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D015032:Zinc
J Am Chem Soc. 2008 Jan 30;130(4):1376-83
18179213
Biophys J. 2009 Aug 19;97(4):1168-77
19686665
J Phys Chem B. 2007 Jul 5;111(26):7646-55
17564430
J Biol Chem. 2008 Apr 18;283(16):10784-92
18234670
Protein Sci. 2000 Jan;9(1):10-9
10739242
Proteins. 2001 Feb 1;42(2):217-29
11119646
Proc Natl Acad Sci U S A. 1985 Jun;82(12):4245-9
3159021
Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17342-7
16293696
J Phys Chem B. 2007 Dec 13;111(49):13814-21
18001084
Inorg Chem. 2009 Jul 6;48(13):5801-9
19496588
Eur J Biochem. 2000 Nov;267(22):6692-8
11054124
Biochem Biophys Res Commun. 2001 Jul 27;285(4):959-64
11467845
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W363-7
15980490
Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11287-92
15269345
Protein Sci. 1999 Jun;8(6):1181-90
10386868
Chembiochem. 2005 Sep;6(9):1663-71
16078307
J Phys Chem B. 2008 Jan 10;112(1):100-9
18072760
J Am Chem Soc. 2006 Mar 22;128(11):3540-2
16536526
Biochemistry. 2007 Nov 27;46(47):13523-32
17973493
J Phys Chem B. 2009 Jan 15;113(2):531-5
19132862
J Phys Chem B. 2007 Apr 12;111(14):3789-99
17388547
Science. 2002 Jul 19;297(5580):353-6
12130773
Biochim Biophys Acta. 2006 Feb;1764(2):246-56
16266835
Science. 1994 Sep 2;265(5177):1464-7
8073293
Chembiochem. 2007 Jan 22;8(2):163-5
17195250
Biochemistry. 2006 Jan 17;45(2):498-512
16401079
Aging (Milano). 2001 Jun;13(3):171-82
11442300
J Biol Inorg Chem. 2009 Mar;14(3):449-55
19083027
Dalton Trans. 2009 Feb 21;(7):1080-94
19322475
Chem Rev. 2010 Aug 11;110(8):4820-38
20402519
J Biol Chem. 2001 Jun 8;276(23):20466-73
11274207
J Comput Chem. 2003 Aug;24(11):1348-56
12827676
Biochemistry. 1999 Jul 20;38(29):9373-8
10413512
J Biol Chem. 2006 Jan 27;281(4):2151-61
16301322
Biochemistry. 2007 Sep 18;46(37):10655-63
17718543
FEBS J. 2007 Jan;274(1):46-59
17222176
Front Biosci (Landmark Ed). 2009 Jun 01;14:5188-238
19482612
Neuroscience. 2007 Dec 5;150(2):357-69
17949919
Biochem Biophys Res Commun. 2006 Jun 23;345(1):210-5
16678130
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11193-4
14506299
J Biol Chem. 1994 Apr 22;269(16):12152-8
8163520
Biochem Biophys Res Commun. 2004 Aug 20;321(2):324-8
15358179
Biochemistry. 2000 Jun 13;39(23):7024-31
10841784
Eur Biophys J. 2006 Apr;35(4):340-51
16404590