A molecular mechanism for transthyretin amyloidogenesis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 02 2019
25 02 2019
Historique:
received:
03
08
2018
accepted:
14
01
2019
entrez:
27
2
2019
pubmed:
26
2
2019
medline:
18
4
2019
Statut:
epublish
Résumé
Human transthyretin (TTR) is implicated in several fatal forms of amyloidosis. Many mutations of TTR have been identified; most of these are pathogenic, but some offer protective effects. The molecular basis underlying the vastly different fibrillation behaviours of these TTR mutants is poorly understood. Here, on the basis of neutron crystallography, native mass spectrometry and modelling studies, we propose a mechanism whereby TTR can form amyloid fibrils via a parallel equilibrium of partially unfolded species that proceeds in favour of the amyloidogenic forms of TTR. It is suggested that unfolding events within the TTR monomer originate at the C-D loop of the protein, and that destabilising mutations in this region enhance the rate of TTR fibrillation. Furthermore, it is proposed that the binding of small molecule drugs to TTR stabilises non-amyloidogenic states of TTR in a manner similar to that occurring for the protective mutants of the protein.
Identifiants
pubmed: 30804345
doi: 10.1038/s41467-019-08609-z
pii: 10.1038/s41467-019-08609-z
pmc: PMC6390107
doi:
Substances chimiques
Prealbumin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
925Références
J Chem Theory Comput. 2012 Oct 9;8(10):3637-49
pubmed: 26593009
Am J Med. 1983 Oct;75(4):618-23
pubmed: 6624768
Biochemistry. 1992 Sep 15;31(36):8654-60
pubmed: 1390650
Acta Crystallogr D Biol Crystallogr. 2012 Apr;68(Pt 4):352-67
pubmed: 22505256
Biophys J. 2012 Aug 22;103(4):786-96
pubmed: 22947940
J Mol Biol. 2005 Apr 8;347(4):841-54
pubmed: 15769474
Proteins. 2010 Jun;78(8):1950-8
pubmed: 20408171
J Comput Chem. 2015 Feb 15;36(5):348-54
pubmed: 25487359
Proc Natl Acad Sci U S A. 2018 Jul 17;115(29):E6741-E6750
pubmed: 29954863
Proteins. 2014 Feb;82(2):195-215
pubmed: 23818175
Angew Chem Int Ed Engl. 2016 Jun 20;55(26):7364-8
pubmed: 27122231
J Comput Chem. 2004 Jul 15;25(9):1157-74
pubmed: 15116359
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Biochemistry. 1996 May 21;35(20):6470-82
pubmed: 8639594
Arch Neurol. 2005 Jul;62(7):1057-62
pubmed: 16009758
J Comput Chem. 1999 Jun;20(8):786-798
pubmed: 35619462
Sci Rep. 2015 Jun 25;5:11443
pubmed: 26108284
Biochemistry. 2010 Jan 12;49(1):114-23
pubmed: 19950966
Acta Crystallogr D Biol Crystallogr. 2006 Jan;62(Pt 1):72-82
pubmed: 16369096
Angew Chem Int Ed Engl. 2016 Aug 1;55(32):9292-6
pubmed: 27311939
PeerJ Comput Sci. 2023 Sep 1;9:e1516
pubmed: 37705656
Proc Natl Acad Sci U S A. 1990 Apr;87(7):2843-5
pubmed: 2320592
Acc Chem Res. 2005 Dec;38(12):911-21
pubmed: 16359163
J Neurol. 2014 Jun;261(6):1227-33
pubmed: 24888313
Transplantation. 1998 Jul 27;66(2):229-33
pubmed: 9701270
J Mol Biol. 2001 Mar 2;306(4):733-44
pubmed: 11243784
J Chem Theory Comput. 2015 Aug 11;11(8):3696-713
pubmed: 26574453
J Biol Chem. 2004 Feb 13;279(7):5699-707
pubmed: 14604984
Lancet Neurol. 2011 Dec;10(12):1086-97
pubmed: 22094129
J Pathol. 2005 Jun;206(2):224-32
pubmed: 15810051
Methods Enzymol. 1997;276:307-26
pubmed: 27754618
J Chem Theory Comput. 2012 Jul 10;8(7):2373-82
pubmed: 26588970
EMBO Mol Med. 2015 Aug 18;7(10):1337-49
pubmed: 26286619
Amyloid. 2013 Sep;20(3):142-50
pubmed: 23713495
J Am Chem Soc. 2015 Dec 2;137(47):14930-43
pubmed: 26509924
Anal Chem. 2006 Nov 1;78(21):7473-83
pubmed: 17073415
Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5468-73
pubmed: 23513222
Science. 1965 Aug 13;149(3685):748-50
pubmed: 14330531
J Chem Theory Comput. 2008 Jan;4(1):116-22
pubmed: 26619985
IUCrJ. 2014 Oct 21;1(Pt 6):429-38
pubmed: 25485123
Biophys J. 2015 Oct 20;109(8):1528-32
pubmed: 26488642
Nat Struct Biol. 2000 Sep;7(9):754-7
pubmed: 10966644
Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17874-9
pubmed: 24128758
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1539-44
pubmed: 24474780
J Chem Theory Comput. 2017 Dec 12;13(12):6373-6381
pubmed: 29091438
Protein Sci. 2001 Aug;10(8):1606-13
pubmed: 11468357
EMBO J. 1993 Feb;12(2):743-8
pubmed: 8095018
Eur J Biochem. 1997 Nov 1;249(3):662-8
pubmed: 9395311
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9629-34
pubmed: 22645360
Acta Crystallogr D Biol Crystallogr. 2010 Nov;66(Pt 11):1198-205
pubmed: 21041937
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011 Nov 1;67(Pt 11):1428-31
pubmed: 22102249
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
J Clin Endocrinol Metab. 1993 Aug;77(2):484-8
pubmed: 8102146
J Mol Biol. 1998 Aug 21;281(3):553-64
pubmed: 9698569
Amyloid. 2013 Dec;20(4):221-5
pubmed: 24053266
J Chem Theory Comput. 2012 Sep 11;8(9):3257-3273
pubmed: 23341755
PLoS Comput Biol. 2009 Aug;5(8):e1000480
pubmed: 19714202
Curr Med Chem. 2012;19(15):2324-42
pubmed: 22471981
Anal Chem. 2002 Mar 15;74(6):1402-7
pubmed: 11922310
Curr Opin Neurol. 1996 Oct;9(5):355-9
pubmed: 8894411
Methods Enzymol. 2016;566:113-57
pubmed: 26791978
Angew Chem Int Ed Engl. 2016 Dec 23;55(52):16168-16171
pubmed: 27885756
Am J Med Genet. 1991 Jun 15;39(4):442-52
pubmed: 1877623
J Biol Chem. 1998 Sep 18;273(38):24715-22
pubmed: 9733771
J Mol Biol. 2000 Sep 22;302(3):649-69
pubmed: 10986125
J Chem Phys. 2007 Jan 7;126(1):014101
pubmed: 17212484