Structural biology of presenilin 1 complexes

Molecular Neurodegeneration

Peter H St George-Hyslop¹  Paul E Fraser¹  Gerold Schmitt-Ulms¹  Seema Qamar²  Fusheng Chen¹  Roger Dodd²  Christopher Bohm¹  Yi Li² 

[1] Tanz Centre for Research in Neurodegenerative Diseases and Depts of Medicine, Laboratory Medicine and Pathobiology and Medical Biophysics, University of Toronto, Krembil Discovery Tower, 6th Floor- 6KD417, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada;Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrookes Hospital, Hills Road, Cambridge CB2 0XY, UK

关键词: Lateral gate;    Gamma-secretase modulator compounds;    Gamma-secretase inhibitor compounds;    Structural biology;    Abeta;    APP;    Notch;    Epsilon secretase;    Gamma-secretase;    PEN-2;    APH1;    Nicastrin;    Presenilin;   

Others  :  1138619
DOI  :  10.1186/1750-1326-9-59

 received in 2014-11-07, accepted in 2014-12-12,  发布年份 2014

【 摘 要 】

The presenilin genes were first identified as the site of missense mutations causing early onset autosomal dominant familial Alzheimer's disease. Subsequent work has shown that the presenilin proteins are the catalytic subunits of a hetero-tetrameric complex containing APH1, nicastrin and PEN-2. This complex (variously termed presenilin complex or gamma-secretase complex) performs an unusual type of proteolysis in which the transmembrane domains of Type I proteins are cleaved within the hydrophobic compartment of the membrane. This review describes some of the molecular and structural biology of this unusual enzyme complex. The presenilin complex is a bilobed structure. The head domain contains the ectodomain of nicastrin. The base domain contains a central cavity with a lateral cleft that likely provides the route for access of the substrate to the catalytic cavity within the centre of the base domain. There are reciprocal allosteric interactions between various sites in the complex that affect its function. For instance, binding of Compound E, a peptidomimetic inhibitor to the PS1 N-terminus, induces significant conformational changes that reduces substrate binding at the initial substrate docking site, and thus inhibits substrate cleavage. However, there is a reciprocal allosteric interaction between these sites such that prior binding of the substrate to the initial docking site paradoxically increases the binding of the Compound E peptidomimetic inhibitor. Such reciprocal interactions are likely to form the basis of a gating mechanism that underlies access of substrate to the catalytic site. An increasingly detailed understanding of the structural biology of the presenilin complex is an essential step towards rational design of substrate- and/or cleavage site-specific modulators of presenilin complex function.

【 授权许可】

   
2014 Li et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]De Strooper B, Iwatsubo T, Wolfe MS: Presenilins and gamma-secretase: structure, function, and role in Alzheimer disease. Cold Spring Harb Perspect Med 2012, 2:a006304.
• [2]Li H, Wolfe MS, Selkoe DJ: Toward structural elucidation of the gamma-secretase complex. Structure 2009, 17:326-334.
• [3]Haass C, Kaether C, Thinakaran G, Sisodia S: Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2012, 2:a006270.
• [4]Wolfe MS: Processive proteolysis by gamma-secretase and the mechanism of Alzheimer's disease. Biol Chem 2012, 393:899-905.
• [5]Chow VW, Mattson MP, Wong PC, Gleichmann M: An overview of APP processing enzymes and products. Neuromolecular Med 2010, 12:1-12.
• [6]Weidemann A, Eggert S, Reinhard FB, Vogel M, Paliga K, Baier G, Masters CL, Beyreuther K, Evin G: A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with notch processing. Biochemistry 2002, 41:2825-2835.
• [7]Yang DS, Tandon A, Chen F, Yu G, Yu H, Arawaka S, Hasegawa H, Duthie M, Schmidt SD, Ramabhadran TV, Nixon RA, Mathews PM, Gandy SE, Mount HT, St George-Hyslop P, Fraser PE: Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins. J Biol Chem 2002, 277:28135-28142.
• [8]Gu Y, Chen F, Sanjo N, Kawarai T, Hasegawa H, Duthie M, Li W, Ruan X, Luthra A, Mount HT, Tandon A, Fraser PE, St George-Hyslop P: APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin-nicastrin complexes. J Biol Chem 2003, 278:7374-7380.
• [9]Fuwa H, Takahashi Y, Konno Y, Watanabe N, Miyashita H, Sasaki M, Natsugari H, Kan T, Fukuyama T, Tomita T, Iwatsubo T: Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic gamma-secretase inhibitors. ACS Chem Biol 2007, 2:408-418.
• [10]Tomita T, Iwatsubo T: Structural biology of presenilins and signal peptide peptidases. J Biol Chem 2013, 288:14673-14680.
• [11]Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y: gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci 2009, 29:13042-13052.
• [12]Zhao G, Mao G, Tan J, Dong Y, Cui MZ, Kim SH, Xu X: Identification of a new presenilin-dependent zeta-cleavage site within the transmembrane domain of amyloid precursor protein. J Biol Chem 2004, 279:50647-50650.
• [13]Zhao G, Cui MZ, Mao G, Dong Y, Tan J, Sun L, Xu X: Gamma-cleavage is dependent on zeta-cleavage during the proteolytic processing of amyloid precursor protein within its transmembrane domain. J Biol Chem 2005, 280:37689-37697.
• [14]Zhao G, Tan J, Mao G, Cui MZ, Xu X: The same gamma-secretase accounts for the multiple intramembrane cleavages of APP. J Neurochem 2007, 100:1234-1246.
• [15]Matsumura N, Takami M, Okochi M, Wada-Kakuda S, Fujiwara H, Tagami S, Funamoto S, Ihara Y, Morishima-Kawashima M: gamma-Secretase associated with lipid rafts: multiple interactive pathways in the stepwise processing of beta-carboxyl-terminal fragment. J Biol Chem 2014, 289:5109-5121.
• [16]Okochi M, Tagami S, Yanagida K, Takami M, Kodama TS, Mori K, Nakayama T, Ihara Y, Takeda M: gamma-secretase modulators and presenilin 1 mutants act differently on presenilin/gamma-secretase function to cleave Abeta42 and Abeta43. Cell Rep 2013, 3:42-51.
• [17]Takamura A, Kawarabayashi T, Yokoseki T, Shibata M, Morishima-Kawashima M, Saito Y, Murayama S, Ihara Y, Abe K, Shoji M, Michikawa M, Matsubara E: Dissociation of beta-amyloid from lipoprotein in cerebrospinal fluid from Alzheimer's disease accelerates beta-amyloid-42 assembly. J Neurosci Res 2011, 89:815-821.
• [18]Mori K, Okochi M, Tagami S, Nakayama T, Yanagida K, Kodama TS, Tatsumi S, Fujii K, Tanimukai H, Hashimoto R, Morihara T, Tanaka T, Kudo T, Funamoto S, Ihara Y, Takeda M: The production ratios of AICDepsilon51 and Abeta42 by intramembrane proteolysis of betaAPP do not always change in parallel. Psychogeriatrics Off J Japanese Psychogeriatric Soc 2010, 10:117-123.
• [19]Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, Iwatsubo T, Kudo T, Takeda M, Haass C: Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. Embo J 2002, 21:5408-5416.
• [20]Mucke L, Selkoe DJ: Neurotoxicity of Amyloid beta-Protein: Synaptic and Network Dysfunction. Cold Spring Harb Perspect Med 2012, 2:a006338.
• [21]Kounnas MZ, Danks AM, Cheng S, Tyree C, Ackerman E, Zhang X, Ahn K, Nguyen P, Comer D, Mao L, Yu C, Pleynet D, Digregorio PJ, Velicelebi G, Stauderman KA, Comer WT, Mobley WC, Li YM, Sisodia SS, Tanzi RE, Wagner SL: Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease. Neuron 2010, 67:769-780.
• [22]Hall A, Patel TR: gamma-Secretase modulators: current status and future directions. Prog Med Chem 2014, 53:101-145.
• [23]Pettersson M, Stepan AF, Kauffman GW, Johnson DS: Novel gamma-secretase modulators for the treatment of Alzheimer's disease: a review focusing on patents from 2010 to 2012. Expert Opin Ther Pat 2013, 23:1349-1366.
• [24]Golde TE, Koo EH, Felsenstein KM, Osborne BA, Miele L: gamma-Secretase inhibitors and modulators. Biochim Biophys Acta 1828, 2013:2898-2907.
• [25]Imbimbo BP, Giardina GA: gamma-secretase inhibitors and modulators for the treatment of Alzheimer's disease: disappointments and hopes. Curr Top Med Chem 2011, 11:1555-1570.
• [26]Cummings J: What can be inferred from the interruption of the semagacestat trial for treatment of Alzheimer's disease? Biol Psychiatry 2010, 68:876-878.
• [27]Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995, 375:754-760.
• [28]Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al.: Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 1995, 376:775-778.
• [29]Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P: TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature 2006, 440:1208-1212.
• [30]De Strooper B: Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 2003, 38:9-12.
• [31]Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ: Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 1999, 398:513-517.
• [32]Dries DR, Yu G: Assembly, maturation, and trafficking of the gamma-secretase complex in Alzheimer's disease. Curr Alzheimer Res 2008, 5:132-146.
• [33]Nishimura MYG, St George-Hyslop PH: Biology of presenilins as causative molecules for Alzheimer disease. Clin Genet 1999, 55:7.
• [34]Fraser PE, Yang DS, Yu G, Levesque L, Nishimura M, Arawaka S, Serpell LC, Rogaeva E, St George-Hyslop P: Presenilin structure, function and role in Alzheimer disease. Biochim Biophys Acta 2000, 1502:1-15.
• [35]Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P: Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000, 407:48-54.
• [36]Li Y, Lu SH, Tsai CJ, Bohm C, Qamar S, Dodd RB, Meadows W, Jeon A, McLeod A, Chen F, Arimon M, Berezovska O, Hyman BT, Tomita T, Iwatsubo T, Johnson CM, Farrer LA, Schmitt-Ulms G, Fraser PE, St George-Hyslop PH: Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes. Structure 2014, 22:125-135.
• [37]Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS: Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 1996, 17:181-190.
• [38]Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B: Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 2002, 296:2215-2218.
• [39]Martoglio B, Golde TE: Intramembrane-cleaving aspartic proteases and disease: presenilins, signal peptide peptidase and their homologs. Hum Mol Genet 2003, 12(2):R201-206.
• [40]Friedmann E, Lemberg MK, Weihofen A, Dev KK, Dengler U, Rovelli G, Martoglio B: Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins. J Biol Chem 2004, 279:50790-50798.
• [41]Fluhrer R, Steiner H, Haass C: Intramembrane proteolysis by signal peptide peptidases: a comparative discussion of GXGD-type aspartyl proteases. J Biol Chem 2009, 284:13975-13979.
• [42]Lu SH, Jeon AH, Schmitt-Ulms G, Qamar S, Dodd R, McDonald B, Li Y, Meadows W, Cox K, Bohm C, Chen F, Fraser P, George-Hyslop PS: Vigilin interacts with signal peptide peptidase. Proteome Sci 2012, 10:33.
• [43]De Strooper B, Annaert W: Novel research horizons for presenilins and gamma-secretases in cell biology and disease. Annu Rev Cell Dev Biol 2010, 26:235-260.
• [44]Steiner H, Fluhrer R, Haass C: Intramembrane proteolysis by gamma-secretase. J Biol Chem 2008, 283:29627-29631.
• [45]Podlisny MB, Citron M, Amarante P, Sherrington R, Xia W, Zhang J, Diehl T, Levesque G, Fraser P, Haass C, Koo EH, Seubert P, St George-Hyslop P, Teplow DB, Selkoe DJ: Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol Dis 1997, 3:325-337.
• [46]Laudon H, Hansson EM, Melen K, Bergman A, Farmery MR, Winblad B, Lendahl U, von Heijne G, Naslund J: A nine-transmembrane domain topology for presenilin 1. J Biol Chem 2005, 280:35352-35360.
• [47]Oh YS, Turner RJ: Topology of the C-terminal fragment of human presenilin 1. Biochemistry 2005, 44:11821-11828.
• [48]Wolfe MS: Toward the structure of presenilin/gamma-secretase and presenilin homologs. Biochim Biophys Acta 1828, 2013:2886-2897.
• [49]Doan A, Thinakaran G, Borchelt DR, Slunt HH, Ratovitsky T, Podlisny M, Selkoe DJ, Seeger M, Gandy SE, Price DL, Sisodia SS: Protein topology of presenilin 1. Neuron 1996, 17:1023-1030.
• [50]Watanabe N, Image I II, Takagi S, Tominaga A, Image Image I, Tomita T, Iwatsubo T: Functional analysis of the transmembrane domains of presenilin 1: participation of transmembrane domains 2 and 6 in the formation of initial substrate-binding site of gamma-secretase. J Biol Chem 2010, 285:19738-19746.
• [51]Sobhanifar S, Schneider B, Lohr F, Gottstein D, Ikeya T, Mlynarczyk K, Pulawski W, Ghoshdastider U, Kolinski M, Filipek S, Guntert P, Bernhard F, Dotsch V: Structural investigation of the C-terminal catalytic fragment of presenilin 1. Proc Natl Acad Sci U S A 2010, 107:9644-9649.
• [52]Li X, Dang S, Yan C, Gong X, Wang J, Shi Y: Structure of a presenilin family intramembrane aspartate protease. Nature 2013, 493:56-61.
• [53]Zhang YW, Luo WJ, Wang H, Lin P, Vetrivel KS, Liao F, Li F, Wong PC, Farquhar MG, Thinakaran G, Xu H: Nicastrin is critical for stability and trafficking but not association of other presenilin/gamma-secretase components. J Biol Chem 2005, 280:17020-17026.
• [54]Shirotani K, Edbauer D, Capell A, Schmitz J, Steiner H, Haass C: Gamma-secretase activity is associated with a conformational change of nicastrin. J Biol Chem 2003, 278:16474-16477.
• [55]Spasic D, Raemaekers T, Dillen K, Declerck I, Baert V, Serneels L, Fullekrug J, Annaert W: Rer1p competes with APH-1 for binding to nicastrin and regulates gamma-secretase complex assembly in the early secretory pathway. J Cell Biol 2007, 176:629-640.
• [56]Chen F, Yu G, Arawaka S, Nishimura M, Kawarai T, Yu H, Tandon A, Supala A, Song YQ, Rogaeva E, Milman P, Sato C, Yu C, Janus C, Lee J, Song L, Zhang L, Fraser PE, St George-Hyslop PH: Nicastrin binds to membrane-tethered Notch. Nat Cell Biol 2001, 3:751-754.
• [57]Shah S, Lee SF, Tabuchi K, Hao YH, Yu C, Laplant Q, Ball H, Dann CE 3rd, Sudhof T, Yu G: Nicastrin Functions as a gamma-Secretase-Substrate Receptor. Cell 2005, 122:435-447.
• [58]Bergman A, Laudon H, Winblad B, Lundkvist J, Naslund J: The extreme C terminus of presenilin 1 is essential for gamma-secretase complex assembly and activity. J Biol Chem 2004, 279:45564-45572.
• [59]Fagan R, Swindells M, Overington J, Weir M: Nicastrin, a presenilin-interacting protein, contains an aminopeptidase/transferrin receptor superfamily domain. Trends Biochem Sci 2001, 26:213-214.
• [60]Lu P, Bai XC, Ma D, Xie T, Yan C, Sun L, Yang G, Zhao Y, Zhou R, Scheres SH, Shi Y: Three-dimensional structure of human gamma-secretase. Nature 2014, 512:166-170.
• [61]Xie T, Yan C, Zhou R, Zhao Y, Sun L, Yang G, Lu P, Ma D, Shi Y: Crystal structure of the gamma-secretase component nicastrin. Proc Natl Acad Sci U S A 2014, 111:13349-13354.
• [62]Zhang X, Hoey RJ, Lin G, Koide A, Leung B, Ahn K, Dolios G, Paduch M, Ikeuchi T, Wang R, Li YM, Koide S, Sisodia SS: Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of gamma-secretase using synthetic antibodies. Proc Natl Acad Sci U S A 2012, 109:8534-8539.
• [63]Fluhrer R, Kamp F, Grammer G, Nuscher B, Steiner H, Beyer K, Haass C: The Nicastrin ectodomain adopts a highly thermostable structure. Biol Chem 2011, 392:995-1001.
• [64]Zhao G, Liu Z, Ilagan MX, Kopan R: Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin. J Neurosci 2010, 30:1648-1656.
• [65]Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M, Maxwell M, Hai B, Ellis MC, Parks AL, Xu W, Li J, Gurney M, Myers RL, Himes CS, Hiebsch R, Ruble C, Nye JS, Curtis D: aph-1 and pen-2 are required for Notch pathway signaling, gamma- secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 2002, 3:85-97.
• [66]Crystal AS, Morais VA, Pierson TC, Pijak DS, Carlin D, Lee VM, Doms RW: Membrane topology of gamma-secretase component PEN-2. J Biol Chem 2003, 278:20117-20123.
• [67]Watanabe N, Tomita T, Sato C, Kitamura T, Morohashi Y, Iwatsubo T: Pen-2 is incorporated into the gamma-secretase complex through binding to transmembrane domain 4 of presenilin 1. J Biol Chem 2005, 280:41967-41975.
• [68]Kim SH, Sisodia SS: A sequence within the first transmembrane domain of PEN-2 is critical for PEN-2-mediated endoproteolysis of presenilin 1. J Biol Chem 2005, 280:1992-2001.
• [69]Kim SH, Sisodia SS: Evidence that the "NF" motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2. J Biol Chem 2005, 280:41953-41966.
• [70]Prokop S, Shirotani K, Edbauer D, Haass C, Steiner H: Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment heterodimer within the gamma-secretase complex. J Biol Chem 2004, 279:23255-23261.
• [71]Holmes O, Paturi S, Selkoe DJ, Wolfe MS: Pen-2 is essential for gamma-secretase complex stability and trafficking but partially dispensable for endoproteolysis. Biochemistry 2014, 53:4393-4406.
• [72]Serneels L, Van Biervliet J, Craessaerts K, Dejaegere T, Horre K, Van Houtvin T, Esselmann H, Paul S, Schafer MK, Berezovska O, Hyman BT, Sprangers B, Sciot R, Moons L, Jucker M, Yang Z, May PC, Karran E, Wiltfang J, D'Hooge R, De Strooper B: gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease. Science 2009, 324:639-642.
• [73]Lee SF, Shah S, Yu C, Wigley WC, Li H, Lim M, Pedersen K, Han W, Thomas P, Lundkvist J, Hao YH, Yu G: A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex. J Biol Chem 2004, 279:4144-4152.
• [74]Fortna RR, Crystal AS, Morais VA, Pijak DS, Lee VM, Doms RW: Membrane topology and nicastrin-enhanced endoproteolysis of APH-1, a component of the gamma-secretase complex. J Biol Chem 2004, 279:3685-3693.
• [75]Pardossi-Piquard R, Yang SP, Kanemoto S, Gu Y, Chen F, Bohm C, Sevalle J, Li T, Wong PC, Checler F, Schmitt-Ulms G, St George-Hyslop P, Fraser PE: APH1 polar transmembrane residues regulate the assembly and activity of presenilin complexes. J Biol Chem 2009, 284:16298-16307.
• [76]Gu Y, Sanjo N, Chen F, Hasegawa H, Petit A, Ruan X, Li W, Shier C, Kawarai T, Schmitt-Ulms G, Westaway D, St George-Hyslop P, Fraser PE: The presenilin proteins are components of multiple membrane-bound complexes that have different biological activities. J Biol Chem 2004, 279:31329-31336.
• [77]Mao G, Cui MZ, Li T, Jin Y, Xu X: Pen-2 is dispensable for endoproteolysis of presenilin 1, and nicastrin-Aph subcomplex is important for both gamma-secretase assembly and substrate recruitment. J Neurochem 2012, 123:837-844.
• [78]Lee SF, Shah S, Li H, Yu C, Han W, Yu G: Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch. J Biol Chem 2002, 277:45013-45019.
• [79]Renzi F, Zhang X, Rice WJ, Torres-Arancivia C, Gomez-Llorente Y, Diaz R, Ahn K, Yu C, Li YM, Sisodia SS, Ubarretxena-Belandia I: Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy. J Biol Chem 2011, 286:21440-21449.
• [80]Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H: Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores. Proc Natl Acad Sci U S A 2006, 103:6889-6894.
• [81]Osenkowski P, Li H, Ye W, Li D, Aeschbach L, Fraering PC, Wolfe MS, Selkoe DJ: Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution. J Mol Biol 2009, 385:642-652.
• [82]Ogura T, Mio K, Hayashi I, Miyashita H, Fukuda R, Kopan R, Kodama T, Hamakubo T, Iwatsubo T, Tomita T, Sato C: Three-dimensional structure of the gamma-secretase complex. Biochem Biophys Res Commun 2006, 343:525-534.
• [83]Wang Y, Maegawa S, Akiyama Y, Ha Y: The role of L1 loop in the mechanism of rhomboid intramembrane protease GlpG. J Mol Biol 2007, 374:1104-1113.
• [84]Bondar AN, del Val C, White SH: Rhomboid protease dynamics and lipid interactions. Structure 2009, 17:395-405.
• [85]Lu P, Bai XC, Ma D, Xie T, Yan C, Sun L, Yang G, Zhao Y, Zhou R, Scheres SH, Shi Y: Three-dimensional structure of human gamma-secretase. Nature 2014.
• [86]Fraering PC, LaVoie MJ, Ye W, Ostaszewski BL, Kimberly WT, Selkoe DJ, Wolfe MS: Detergent-dependent dissociation of active gamma-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex. Biochemistry 2004, 43:323-333.
• [87]Barthet G, Shioi J, Shao Z, Ren Y, Georgakopoulos A, Robakis NK: Inhibitors of gamma-secretase stabilize the complex and differentially affect processing of amyloid precursor protein and other substrates. FASEB J 2011, 25:2937-2946.
• [88]Miyashita H, Maruyama Y, Isshiki H, Osawa S, Ogura T, Mio K, Sato C, Tomita T, Iwatsubo T: Three-dimensional structure of the signal peptide peptidase. J Biol Chem 2011, 286:26188-26197.