title: The effect of β2-α2 loop mutation on amyloidogenic properties of the prion protein.
abstract: Recent studies revealed that elk-like S170N/N174T mutation in mouse prion protein (moPrP), which results in an increased rigidity of β2-α2 loop, leads to a prion disease in transgenic mice. Here we characterized the effect of this mutation on biophysical properties of moPrP. Despite similar thermodynamic stabilities of wild type and mutant proteins, the latter was found to have markedly higher propensity to form amyloid fibrils. Importantly, this effect was observed even under fully denaturing conditions, indicating that the increased conversion propensity of the mutant protein is not due to loop rigidity but rather results from greater amyloidogenic potential of the amino acid sequence within the loop region of S170N/N174T moPrP.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Arpana
authors.initials: A
authors.lastname: Dutta
authors.forename: Shugui
authors.initials: S
authors.lastname: Chen
authors.forename: Witold K
authors.initials: WK
authors.lastname: Surewicz
mesh_terms: D020816:Amino Acid Motifs; D058227:Amyloidogenic Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D000818:Animals; D015870:Gene Expression; D051379:Mice; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D008958:Models, Molecular; D009154:Mutation; D018621:PrPC Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure; D012996:Solutions; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D058227:Amyloidogenic Proteins; D018621:PrPC Proteins; D011994:Recombinant Proteins; D012996:Solutions
keywords: Amyloid; GuHCl; PrP; Prion disease; Prion protein; Protein structure; ThT; guanidine hydrochloride; moPrP; mouse prion protein; prion protein; thioflavin T; wild type; wt
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1510-5
references.pmid: 17242357
references.citation: Biochemistry. 2005 Dec 6;44(48):15880-8
references.pmid: 16313190
references.citation: Nature. 2007 May 24;447(7143):453-7
references.pmid: 17468747
references.citation: J Biol Chem. 1999 Dec 24;274(52):36859-65
references.pmid: 10601237
references.citation: Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):145-50
references.pmid: 10618385
references.citation: J Gen Virol. 2006 Aug;87(Pt 8):2443-2449
references.pmid: 16847141
references.citation: Proc Natl Acad Sci U S A. 2012 May 29;109(22):8546-51
references.pmid: 22586108
references.citation: J Mol Biol. 2004 Aug 6;341(2):575-88
references.pmid: 15276845
references.citation: J Mol Biol. 2008 Feb 29;376(4):1155-67
references.pmid: 18206163
references.citation: Prion. 2007 Jul-Sep;1(3):185-97
references.pmid: 19164911
references.citation: Cell. 2005 Apr 8;121(1):63-72
references.pmid: 15820679
references.citation: Adv Protein Chem. 2001;57:55-82
references.pmid: 11447697
references.citation: Nat Struct Mol Biol. 2011 Apr;18(4):504-6
references.pmid: 21441913
references.citation: J Am Chem Soc. 2006 Sep 6;128(35):11673-8
references.pmid: 16939293
references.citation: J Mol Biol. 2005 Feb 18;346(2):645-59
references.pmid: 15670611
references.citation: FEBS Lett. 1997 Aug 18;413(2):282-8
references.pmid: 9280298
references.citation: Nat Struct Mol Biol. 2009 Sep;16(9):973-8
references.pmid: 19684598
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):640-5
references.pmid: 15647367
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):646-50
references.pmid: 15647363
references.citation: Top Curr Chem. 2011;305:135-67
references.pmid: 21630136
references.citation: Nat Struct Biol. 1999 Aug;6(8):740-3
references.pmid: 10426950
references.citation: Science. 2010 Feb 26;327(5969):1132-5
references.pmid: 20110469
references.citation: Protein Sci. 1993 Mar;2(3):404-10
references.pmid: 8453378
references.citation: Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8334-9
references.pmid: 10899999
references.citation: Nature. 1996 Jul 11;382(6587):180-2
references.pmid: 8700211
references.citation: Acta Neuropathol. 2010 Feb;119(2):177-87
references.pmid: 20052481
references.citation: Science. 2007 Nov 9;318(5852):930-6
references.pmid: 17991853
references.citation: Biochemistry. 2009 Mar 31;48(12):2574-85
references.pmid: 19239250
references.citation: J Biol Chem. 2009 Sep 4;284(36):24233-41
references.pmid: 19596861
references.citation: Cell. 1998 May 1;93(3):337-48
references.pmid: 9590169
references.citation: FASEB J. 2007 Oct;21(12):3279-87
references.pmid: 17522379
references.citation: Biochemistry. 2011 Apr 5;50(13):2456-63
references.pmid: 21323366
references.citation: Biochemistry. 2005 Dec 20;44(50):16649-57
references.pmid: 16342955
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):304-9
references.pmid: 19073920
references.citation: J Biol Chem. 2010 May 7;285(19):14083-7
references.pmid: 20304915
references.citation: J Biol Chem. 2002 Dec 13;277(50):49065-70
references.pmid: 12372829
references.citation: J Mol Biol. 2008 Nov 7;383(2):306-12
references.pmid: 18773909
references.citation: J Biol Chem. 2004 Apr 23;279(17):18008-14
references.pmid: 14761942
references.citation: FASEB J. 2012 Jul;26(7):2868-76
references.pmid: 22490928
references.citation: Biochemistry. 1988 Oct 18;27(21):8063-8
references.pmid: 3233195
references.citation: Science. 2004 Jul 30;305(5684):673-6
references.pmid: 15286374