title: Conformational Changes in Transmembrane Domain 4 of Presenilin 1 Are Associated with Altered Amyloid-β 42 Production.
abstract: γ-Secretase is an intramembrane-cleaving protease that produces amyloid-β peptide 42 (Aβ42), which is the toxic and aggregation-prone species of Aβ that causes Alzheimer's disease. Here, we used the substituted cysteine accessibility method to analyze the structure of transmembrane domains (TMDs) 4 and 5 of human presenilin 1 (PS1), a catalytic subunit of γ-secretase. We revealed that TMD4 and TMD5 face the intramembranous hydrophilic milieu together with TMD1, TMD6, TMD7, and TMD9 of PS1 to form the catalytic pore structure. Notably, we found a correlation in the distance between the cytosolic sides of TMD4/TMD7 and Aβ42 production levels, suggesting that allosteric conformational changes of the cytosolic side of TMD4 affect Aβ42-generating γ-secretase activity. Our results provide new insights into the relationship between the structure and activity of human PS1.
  
  
  CONCLUSIONS
  Modulation of γ-secretase activity to reduce toxic amyloid-β peptide species is one plausible therapeutic approaches for Alzheimer's disease. However, precise mechanistic information of γ-secretase still remains unclear. Here we identified the conformational changes in transmembrane domains of presenilin 1 that affect the proteolytic activity of the γ-secretase. Our results highlight the importance of understanding the structural dynamics of presenilin 1 in drug development against Alzheimer's disease.
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences.
authors.forename: Aya
authors.initials: A
authors.lastname: Tominaga
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, Laboratory of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, and.
authors.forename: Tetsuo
authors.identifier: http://orcid.org/0000-0002-2765-9134
authors.initials: T
authors.lastname: Cai
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Takagi-Niidome
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, and.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Taisuke
authors.identifier: http://orcid.org/0000-0002-0075-5943
authors.initials: T
authors.lastname: Tomita
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D019921:Biotinylation; D020134:Catalytic Domain / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D051881:Receptor, Notch1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases
keywords: allosteric change; amyloid; enzyme; membrane protein; protease; secretase
references.citation: Biophys J. 1999 Sep;77(3):1609-18
references.pmid: 10465772
references.citation: J Neurosci. 1999 Dec 15;19(24):10627-34
references.pmid: 10594046
references.citation: Nature. 2000 Jun 8;405(6787):689-94
references.pmid: 10864326
references.citation: Nat Cell Biol. 2000 Jul;2(7):461-2
references.pmid: 10878813
references.citation: Biochemistry. 2000 Aug 1;39(30):8698-704
references.pmid: 10913280
references.citation: J Neurochem. 2001 Jan;76(1):173-81
references.pmid: 11145990
references.citation: J Biol Chem. 2001 Oct 5;276(40):36877-80
references.pmid: 11518701
references.citation: Neurobiol Dis. 2002 Oct;11(1):64-82
references.pmid: 12460547
references.citation: J Biol Chem. 2003 May 16;278(20):18664-70
references.pmid: 12637581
references.citation: Nature. 2003 Mar 27;422(6930):438-41
references.pmid: 12660785
references.citation: Science. 2003 Aug 1;301(5633):610-5
references.pmid: 12893935
references.citation: J Am Chem Soc. 2003 Oct 1;125(39):11794-5
references.pmid: 14505382
references.citation: Exp Hematol. 2003 Nov;31(11):1007-14
references.pmid: 14585362
references.citation: Bioorg Med Chem Lett. 2004 Apr 19;14(8):1983-5
references.pmid: 15050642
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3230-5
references.pmid: 15722417
references.citation: J Biol Chem. 2005 Dec 23;280(51):41953-66
references.pmid: 16234243
references.citation: J Biol Chem. 2005 Dec 23;280(51):41967-75
references.pmid: 16234244
references.citation: J Biol Chem. 2006 May 26;281(21):14670-6
references.pmid: 16569643
references.citation: J Neurosci. 2006 Nov 15;26(46):12081-8
references.pmid: 17108181
references.citation: J Biol Chem. 2007 Apr 27;282(17):12388-96
references.pmid: 17329245
references.citation: J Neurosci. 2008 Jun 11;28(24):6264-71
references.pmid: 18550769
references.citation: Science. 2009 Mar 27;323(5922):1718-22
references.pmid: 19325113
references.citation: J Biol Chem. 2010 Jun 4;285(23):17798-810
references.pmid: 20348104
references.citation: J Biol Chem. 2010 Jun 25;285(26):19738-46
references.pmid: 20418378
references.citation: J Neurosci. 2010 Nov 24;30(47):15943-50
references.pmid: 21106832
references.citation: J Membr Biol. 2011 Jan;239(1-2):85-93
references.pmid: 21161516
references.citation: J Biol Chem. 2011 Apr 8;286(14):12271-82
references.pmid: 21296884
references.citation: Sci Transl Med. 2011 Apr 6;3(77):77sr1
references.pmid: 21471435
references.citation: EMBO J. 2011 Oct 14;30(23):4815-24
references.pmid: 22002539
references.citation: Hum Mutat. 2012 Sep;33(9):1340-4
references.pmid: 22581678
references.citation: Biochemistry. 2012 Jun 19;51(24):4779-89
references.pmid: 22650985
references.citation: J Biol Chem. 2012 Jul 27;287(31):25834-43
references.pmid: 22689582
references.citation: Structure. 2012 Jul 3;20(7):1255-63
references.pmid: 22705210
references.citation: Nature. 2013 Jan 3;493(7430):56-61
references.pmid: 23254940
references.citation: Cell Rep. 2013 Jan 31;3(1):42-51
references.pmid: 23291095
references.citation: J Biol Chem. 2013 May 24;288(21):14673-80
references.pmid: 23585568
references.citation: Nature. 2014 Aug 14;512(7513):166-170
references.pmid: 25043039
references.citation: J Biochem. 2014 Oct;156(4):195-201
references.pmid: 25108625
references.citation: J Cell Sci. 2015 Feb 1;128(3):589-98
references.pmid: 25501811
references.citation: Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5063-8
references.pmid: 25855636
references.citation: Nature. 2015 Sep 10;525(7568):212-217
references.pmid: 26280335
references.citation: Elife. 2015 Dec 01;4:null
references.pmid: 26623517
references.citation: Biochim Biophys Acta. 1968 May;158(2):239-45
references.pmid: 4871609
references.citation: Nat Genet. 1995 Oct;11(2):219-22
references.pmid: 7550356
references.citation: Biochemistry. 1995 Aug 15;34(32):10272-8
references.pmid: 7640283
references.citation: Neuron. 1994 Jul;13(1):45-53
references.pmid: 8043280
references.citation: Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1683-8
references.pmid: 8643690
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):2025-30
references.pmid: 9050898
references.citation: Neuroreport. 1998 Jan 26;9(2):217-21
references.pmid: 9507958
references.citation: J Neurochem. 1999 Jan;72(1):255-61
references.pmid: 9886077