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- W1963923664 abstract "Presenilin 1 (PS1) and presenilin 2 (PS2) are endoproteolytically processed in vivo and in cell transfectants to yield 27–35-kDa N-terminal and 15–24-kDa C-terminal fragments. We have studied the cleavage of PS1 and PS2 in transiently and stably transfected hamster kidney and mouse and human neuroblastoma cells by immunoblot and pulse-chase experiments. C-terminal fragments were isolated by affinity chromatography and SDS-polyacrylamide gel electrophoresis and sequenced. The processing sites identified in PS1 and PS2 (Asp345/Ser346 and Asp329/Ser330, respectively) are typical for caspase-type proteases. Specific caspase inhibitors and cleavage site mutations confirmed the involvement of caspase(s) in PS1 and PS2 processing in cell transfectants. Fluorescent peptide substrates carrying the PS-identified cleavage sites were hydrolyzed by proteolytic activity from mouse brain. The PS2-derived peptide substrate was also cleaved by recombinant human caspase-3. Additional processing of PS2 by non-caspase-type proteases was also observed. Presenilin 1 (PS1) and presenilin 2 (PS2) are endoproteolytically processed in vivo and in cell transfectants to yield 27–35-kDa N-terminal and 15–24-kDa C-terminal fragments. We have studied the cleavage of PS1 and PS2 in transiently and stably transfected hamster kidney and mouse and human neuroblastoma cells by immunoblot and pulse-chase experiments. C-terminal fragments were isolated by affinity chromatography and SDS-polyacrylamide gel electrophoresis and sequenced. The processing sites identified in PS1 and PS2 (Asp345/Ser346 and Asp329/Ser330, respectively) are typical for caspase-type proteases. Specific caspase inhibitors and cleavage site mutations confirmed the involvement of caspase(s) in PS1 and PS2 processing in cell transfectants. Fluorescent peptide substrates carrying the PS-identified cleavage sites were hydrolyzed by proteolytic activity from mouse brain. The PS2-derived peptide substrate was also cleaved by recombinant human caspase-3. Additional processing of PS2 by non-caspase-type proteases was also observed. Mutant presenilin 1 and 2 (PS1,PS2) 1The abbreviations used are: PS1, presenilin 1; PS2, presenilin 2; FAD, familial Alzheimer's disease; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; BHK, baby hamster kidney; CHO, Chinese hamster ovary; SFV, Semliki Forest virus; PAGE, polyacrylamide gel electrophoresis; AMC, aminomethylcoumarin; Ac-DEVD-AMC, Ac-Asp-Glu-Val-Asp-AMC; Ac-DSYD-AMC, Ac-Asp-Ser-Tyr-Asp-AMC; Ac-AQRD-AMC, Ac-Ala-Gln-Arg-Asp-AMC; b-DEVD-CHO, biotinyl-Asp-Glu-Val-Asp-aldehyde; b-DSYD-CHO, biotinyl-amidocaproyl-Asp-Ser-Tyr-Asp-aldehyde; b-AQRD-CHO, biotinyl-amidocaproyl-Ala-Gln-Arg-Asp-aldehyde; Ac-YVAD-dbmk, Ac-Tyr-Val-Ala-Asp-dimethylbenzoyloxymethyl ketone; TLCK,N α-p-tosyl-l-lysine chloromethyl ketone; ER, endoplasmic reticulum; PCR, polymerase chain reaction. 1The abbreviations used are: PS1, presenilin 1; PS2, presenilin 2; FAD, familial Alzheimer's disease; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; BHK, baby hamster kidney; CHO, Chinese hamster ovary; SFV, Semliki Forest virus; PAGE, polyacrylamide gel electrophoresis; AMC, aminomethylcoumarin; Ac-DEVD-AMC, Ac-Asp-Glu-Val-Asp-AMC; Ac-DSYD-AMC, Ac-Asp-Ser-Tyr-Asp-AMC; Ac-AQRD-AMC, Ac-Ala-Gln-Arg-Asp-AMC; b-DEVD-CHO, biotinyl-Asp-Glu-Val-Asp-aldehyde; b-DSYD-CHO, biotinyl-amidocaproyl-Asp-Ser-Tyr-Asp-aldehyde; b-AQRD-CHO, biotinyl-amidocaproyl-Ala-Gln-Arg-Asp-aldehyde; Ac-YVAD-dbmk, Ac-Tyr-Val-Ala-Asp-dimethylbenzoyloxymethyl ketone; TLCK,N α-p-tosyl-l-lysine chloromethyl ketone; ER, endoplasmic reticulum; PCR, polymerase chain reaction. genes are linked to early-onset familial Alzheimer's disease (1Sherrington R. Rogaev E.I. Liang Y. Rogaeva E.A. Levesque G. Ikeda M. Chi H. Lin C. Li G. Holman K. et al.Nature. 1995; 375: 754-760Crossref PubMed Scopus (3556) Google Scholar, 2Rogaev E.I. Sherrington R. Rogaeva E.A. Levesque G. Ikeda M. Liang Y. Chi H. Lin C. Holman K. Tsuda T. et al.Nature. 1995; 376: 775-778Crossref PubMed Scopus (1774) Google Scholar, 3Tanzi R.E. Kovacs D.M. Kim T.-W. Moir R.D. Guenette S.Y. Wasco W. Alzheimer's Dis. Rev. 1996; 1: 90-98Google Scholar, 4Haass C. Curr. Opin. Neurol. 1996; 9: 254-259Crossref PubMed Scopus (50) Google Scholar, 5Levy-Lahad E. Wasco W. Poorkaj P. Romano D.M. Oshima J. Pettingell W.H. Yu C. Jondro P.D. Schmidt S.D. Wang K. Crowley A.C. Fu Y.-H. Guenette S.Y. Galas D. Nemens E. Wijsman E.M. Bird T.D. Schellenberg G.D. Tanzi R.E. Science. 1995; 269: 973-977Crossref PubMed Scopus (2213) Google Scholar). The PS gene products are integral membrane proteins localized in Golgi and ER compartments (6Doan A. Thinakaran G. Borchelt D.R. Slunt H.H. Ratovitsky T. Podlisny M. Selkoe D. Seeger M. Gandy S.E. Price D.L. Sisodia S.S. Neuron. 1996; 17: 1023-1030Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar, 7Cook D.G. Sung J.C. Golde T.E. Felsenstein K.M. Wojczyk B.S. Tanzi R.E. Trojanowski J.Q. Lee Virginia M.Y. Doms Robert W. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 9223-9228Crossref PubMed Scopus (182) Google Scholar, 8Walter J. Capell A. Grünberg J. Pesold B. Schindzielorz A. Prior R. Podlisny M.B. Fraser P. St. George Hyslop P. Selkoe D. Haass C. Mol. Med. 1997; 2: 673-691Crossref Google Scholar). They share ∼65% sequence identity and similar structural features, i.e. 6–8 transmembrane domains, hydrophilic regions at their N and C termini, and a large hydrophilic loop C-terminal to transmembrane domain 6 (6Doan A. Thinakaran G. Borchelt D.R. Slunt H.H. Ratovitsky T. Podlisny M. Selkoe D. Seeger M. Gandy S.E. Price D.L. Sisodia S.S. Neuron. 1996; 17: 1023-1030Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar, 9Lehmann S. Chiesak R. Harris D.A. J. Biol. Chem. 1997; 272: 12047-12051Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 10Kim T. Pettingell W.H. Hallmark O.G. Moir R.D. Wasco W. Tanzi R.E. J. Biol. Chem. 1997; 272: 11006-11010Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). The loop and the N terminus are the regions of significant sequence divergence between PS1 and PS2. More than 30 mutations in PS1 and 2 mutations in PS2 have been genetically linked to early-onset FAD (3Tanzi R.E. Kovacs D.M. Kim T.-W. Moir R.D. Guenette S.Y. Wasco W. Alzheimer's Dis. Rev. 1996; 1: 90-98Google Scholar, 4Haass C. Curr. Opin. Neurol. 1996; 9: 254-259Crossref PubMed Scopus (50) Google Scholar). The biological functions of PS currently remain unknown. Studies on the structural homologue in Caenorhabditis elegans, SEL-12, suggest a role in protein trafficking and in the Notchsignaling pathway (11Levitan D. Greenwald I. Nature. 1995; 377: 351-354Crossref PubMed Scopus (625) Google Scholar). Human carriers of PS FAD mutations show a small but significant increase (approximately 1.5–3-fold) in plasma levels of Aβ1–42 compared with normal controls, whereas levels of Aβ1–40 are unchanged (12Xia W. Zhang J. Kholodenko D. Citron M. Podlinsy M.B. Teplow D.B. Haass C. Seubert P. Koo E.H. Selkoe D.J. J. Biol. Chem. 1997; 272: 7977-7982Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 13Tomita T. Maruyama K. Saido T.C. Kume H. Shinozaki K. Tokuhiro S. Capell A. Walter J. Grünberg J. Haass C. Iwatsubo T. Obata K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2025-2030Crossref PubMed Scopus (347) Google Scholar, 14Scheuner D. Eckman C. Jensen M. Song X. Citron M. Suzuki N. Bird T.D. Hardy J. Hutton M. Kukull W. Larson E. Levy Lahad E. Viitanen M. Peskind E. Poorkaj P. Schellenberg G. Tanzi R. Wasco W. Lannfelt L. Selkoe D. Younkin S. Nat. Med. 1996; 2: 864-870Crossref PubMed Scopus (2249) Google Scholar). A specific effect on γ-secretase processing of β-amyloid precursor protein has been proposed, and this enhanced misprocessing of β-amyloid precursor protein is thought to be crucial for FAD pathogenesis. Recent experiments have indicated a regulatory role for PS2 in cell apoptosis. C-terminal fragment of mouse PS2 reportedly protected T-cells or PC12 cells from different apoptosis-inducing challenges, whereas the susceptibility to the same challenges was enhanced when full-length PS2 was overexpressed (15Wolozin B. Iwasaki K. Vito P. Ganjei J.K. Lacanà E. Sunderland T. Zhao B. Kusiak J.W. Wasco W. D'Adamio L. Science. 1996; 274: 1710-1713Crossref PubMed Scopus (390) Google Scholar, 16Vito P. Wolozin B. Ganjei J.K. Iwasaki K. Lacanà E. D'Adamio L. J. Biol. Chem. 1996; 271: 31025-31028Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar).Extensive proteolytic cleavage of PS1 resulting in a 27–28-kDa N-terminal fragment and a 16–17-kDa C-terminal fragment was reported for PS1-transfected COS-1 cells, mice transgenic for human PS1, and endogenous PS1 in human and murine tissues (12Xia W. Zhang J. Kholodenko D. Citron M. Podlinsy M.B. Teplow D.B. Haass C. Seubert P. Koo E.H. Selkoe D.J. J. Biol. Chem. 1997; 272: 7977-7982Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 17Lee M.K. Slunt H.H. Martin L.J. Thinakaran G. Kim G. Gandy S.E. Seeger M. Koo E. Price D.L. Sisodia S.S. J. Neurosci. 1996; 16: 7513-7525Crossref PubMed Google Scholar, 18Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Ratovitsky T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar, 19Ward R.V. Davis J.B. Gray C.W. Barton A.J.L. Bresciani L.G. Caivano M. Murphy V.F. Duff K. Hutton M. Hardy J. Roberts G.W. Karran E.H. Neurodegeneration. 1996; 5: 293-298Crossref PubMed Scopus (31) Google Scholar). Proteolytic processing has also been reported for human PS2 resulting in a 35-kDa N-terminal fragment and a 20-kDa C-terminal peptide (3Tanzi R.E. Kovacs D.M. Kim T.-W. Moir R.D. Guenette S.Y. Wasco W. Alzheimer's Dis. Rev. 1996; 1: 90-98Google Scholar, 10Kim T. Pettingell W.H. Hallmark O.G. Moir R.D. Wasco W. Tanzi R.E. J. Biol. Chem. 1997; 272: 11006-11010Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 13Tomita T. Maruyama K. Saido T.C. Kume H. Shinozaki K. Tokuhiro S. Capell A. Walter J. Grünberg J. Haass C. Iwatsubo T. Obata K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2025-2030Crossref PubMed Scopus (347) Google Scholar). In the present study we have identified proteolytic processing sites in PS1 and PS2 and demonstrate that processing occurs through caspase-type protease(s). We also observed additional, caspase-independent cleavage products suggesting alternative pathways of presenilin processing. Mutant presenilin 1 and 2 (PS1,PS2) 1The abbreviations used are: PS1, presenilin 1; PS2, presenilin 2; FAD, familial Alzheimer's disease; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; BHK, baby hamster kidney; CHO, Chinese hamster ovary; SFV, Semliki Forest virus; PAGE, polyacrylamide gel electrophoresis; AMC, aminomethylcoumarin; Ac-DEVD-AMC, Ac-Asp-Glu-Val-Asp-AMC; Ac-DSYD-AMC, Ac-Asp-Ser-Tyr-Asp-AMC; Ac-AQRD-AMC, Ac-Ala-Gln-Arg-Asp-AMC; b-DEVD-CHO, biotinyl-Asp-Glu-Val-Asp-aldehyde; b-DSYD-CHO, biotinyl-amidocaproyl-Asp-Ser-Tyr-Asp-aldehyde; b-AQRD-CHO, biotinyl-amidocaproyl-Ala-Gln-Arg-Asp-aldehyde; Ac-YVAD-dbmk, Ac-Tyr-Val-Ala-Asp-dimethylbenzoyloxymethyl ketone; TLCK,N α-p-tosyl-l-lysine chloromethyl ketone; ER, endoplasmic reticulum; PCR, polymerase chain reaction. 1The abbreviations used are: PS1, presenilin 1; PS2, presenilin 2; FAD, familial Alzheimer's disease; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; BHK, baby hamster kidney; CHO, Chinese hamster ovary; SFV, Semliki Forest virus; PAGE, polyacrylamide gel electrophoresis; AMC, aminomethylcoumarin; Ac-DEVD-AMC, Ac-Asp-Glu-Val-Asp-AMC; Ac-DSYD-AMC, Ac-Asp-Ser-Tyr-Asp-AMC; Ac-AQRD-AMC, Ac-Ala-Gln-Arg-Asp-AMC; b-DEVD-CHO, biotinyl-Asp-Glu-Val-Asp-aldehyde; b-DSYD-CHO, biotinyl-amidocaproyl-Asp-Ser-Tyr-Asp-aldehyde; b-AQRD-CHO, biotinyl-amidocaproyl-Ala-Gln-Arg-Asp-aldehyde; Ac-YVAD-dbmk, Ac-Tyr-Val-Ala-Asp-dimethylbenzoyloxymethyl ketone; TLCK,N α-p-tosyl-l-lysine chloromethyl ketone; ER, endoplasmic reticulum; PCR, polymerase chain reaction. genes are linked to early-onset familial Alzheimer's disease (1Sherrington R. Rogaev E.I. Liang Y. Rogaeva E.A. Levesque G. Ikeda M. Chi H. Lin C. Li G. Holman K. et al.Nature. 1995; 375: 754-760Crossref PubMed Scopus (3556) Google Scholar, 2Rogaev E.I. Sherrington R. Rogaeva E.A. Levesque G. Ikeda M. Liang Y. Chi H. Lin C. Holman K. Tsuda T. et al.Nature. 1995; 376: 775-778Crossref PubMed Scopus (1774) Google Scholar, 3Tanzi R.E. Kovacs D.M. Kim T.-W. Moir R.D. Guenette S.Y. Wasco W. Alzheimer's Dis. Rev. 1996; 1: 90-98Google Scholar, 4Haass C. Curr. Opin. Neurol. 1996; 9: 254-259Crossref PubMed Scopus (50) Google Scholar, 5Levy-Lahad E. Wasco W. Poorkaj P. Romano D.M. Oshima J. Pettingell W.H. Yu C. Jondro P.D. Schmidt S.D. Wang K. Crowley A.C. Fu Y.-H. Guenette S.Y. Galas D. Nemens E. Wijsman E.M. Bird T.D. Schellenberg G.D. Tanzi R.E. Science. 1995; 269: 973-977Crossref PubMed Scopus (2213) Google Scholar). The PS gene products are integral membrane proteins localized in Golgi and ER compartments (6Doan A. Thinakaran G. Borchelt D.R. Slunt H.H. Ratovitsky T. Podlisny M. Selkoe D. Seeger M. Gandy S.E. Price D.L. Sisodia S.S. Neuron. 1996; 17: 1023-1030Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar, 7Cook D.G. Sung J.C. Golde T.E. Felsenstein K.M. Wojczyk B.S. Tanzi R.E. Trojanowski J.Q. Lee Virginia M.Y. Doms Robert W. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 9223-9228Crossref PubMed Scopus (182) Google Scholar, 8Walter J. Capell A. Grünberg J. Pesold B. Schindzielorz A. Prior R. Podlisny M.B. Fraser P. St. George Hyslop P. Selkoe D. Haass C. Mol. Med. 1997; 2: 673-691Crossref Google Scholar). They share ∼65% sequence identity and similar structural features, i.e. 6–8 transmembrane domains, hydrophilic regions at their N and C termini, and a large hydrophilic loop C-terminal to transmembrane domain 6 (6Doan A. Thinakaran G. Borchelt D.R. Slunt H.H. Ratovitsky T. Podlisny M. Selkoe D. Seeger M. Gandy S.E. Price D.L. Sisodia S.S. Neuron. 1996; 17: 1023-1030Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar, 9Lehmann S. Chiesak R. Harris D.A. J. Biol. Chem. 1997; 272: 12047-12051Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 10Kim T. Pettingell W.H. Hallmark O.G. Moir R.D. Wasco W. Tanzi R.E. J. Biol. Chem. 1997; 272: 11006-11010Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). The loop and the N terminus are the regions of significant sequence divergence between PS1 and PS2. More than 30 mutations in PS1 and 2 mutations in PS2 have been genetically linked to early-onset FAD (3Tanzi R.E. Kovacs D.M. Kim T.-W. Moir R.D. Guenette S.Y. Wasco W. Alzheimer's Dis. Rev. 1996; 1: 90-98Google Scholar, 4Haass C. Curr. Opin. Neurol. 1996; 9: 254-259Crossref PubMed Scopus (50) Google Scholar). The biological functions of PS currently remain unknown. Studies on the structural homologue in Caenorhabditis elegans, SEL-12, suggest a role in protein trafficking and in the Notchsignaling pathway (11Levitan D. Greenwald I. Nature. 1995; 377: 351-354Crossref PubMed Scopus (625) Google Scholar). Human carriers of PS FAD mutations show a small but significant increase (approximately 1.5–3-fold) in plasma levels of Aβ1–42 compared with normal controls, whereas levels of Aβ1–40 are unchanged (12Xia W. Zhang J. Kholodenko D. Citron M. Podlinsy M.B. Teplow D.B. Haass C. Seubert P. Koo E.H. Selkoe D.J. J. Biol. Chem. 1997; 272: 7977-7982Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 13Tomita T. Maruyama K. Saido T.C. Kume H. Shinozaki K. Tokuhiro S. Capell A. Walter J. Grünberg J. Haass C. Iwatsubo T. Obata K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2025-2030Crossref PubMed Scopus (347) Google Scholar, 14Scheuner D. Eckman C. Jensen M. Song X. Citron M. Suzuki N. Bird T.D. Hardy J. Hutton M. Kukull W. Larson E. Levy Lahad E. Viitanen M. Peskind E. Poorkaj P. Schellenberg G. Tanzi R. Wasco W. Lannfelt L. Selkoe D. Younkin S. Nat. Med. 1996; 2: 864-870Crossref PubMed Scopus (2249) Google Scholar). A specific effect on γ-secretase processing of β-amyloid precursor protein has been proposed, and this enhanced misprocessing of β-amyloid precursor protein is thought to be crucial for FAD pathogenesis. Recent experiments have indicated a regulatory role for PS2 in cell apoptosis. C-terminal fragment of mouse PS2 reportedly protected T-cells or PC12 cells from different apoptosis-inducing challenges, whereas the susceptibility to the same challenges was enhanced when full-length PS2 was overexpressed (15Wolozin B. Iwasaki K. Vito P. Ganjei J.K. Lacanà E. Sunderland T. Zhao B. Kusiak J.W. Wasco W. D'Adamio L. Science. 1996; 274: 1710-1713Crossref PubMed Scopus (390) Google Scholar, 16Vito P. Wolozin B. Ganjei J.K. Iwasaki K. Lacanà E. D'Adamio L. J. Biol. Chem. 1996; 271: 31025-31028Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). Extensive proteolytic cleavage of PS1 resulting in a 27–28-kDa N-terminal fragment and a 16–17-kDa C-terminal fragment was reported for PS1-transfected COS-1 cells, mice transgenic for human PS1, and endogenous PS1 in human and murine tissues (12Xia W. Zhang J. Kholodenko D. Citron M. Podlinsy M.B. Teplow D.B. Haass C. Seubert P. Koo E.H. Selkoe D.J. J. Biol. Chem. 1997; 272: 7977-7982Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 17Lee M.K. Slunt H.H. Martin L.J. Thinakaran G. Kim G. Gandy S.E. Seeger M. Koo E. Price D.L. Sisodia S.S. J. Neurosci. 1996; 16: 7513-7525Crossref PubMed Google Scholar, 18Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Ratovitsky T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar, 19Ward R.V. Davis J.B. Gray C.W. Barton A.J.L. Bresciani L.G. Caivano M. Murphy V.F. Duff K. Hutton M. Hardy J. Roberts G.W. Karran E.H. Neurodegeneration. 1996; 5: 293-298Crossref PubMed Scopus (31) Google Scholar). Proteolytic processing has also been reported for human PS2 resulting in a 35-kDa N-terminal fragment and a 20-kDa C-terminal peptide (3Tanzi R.E. Kovacs D.M. Kim T.-W. Moir R.D. Guenette S.Y. Wasco W. Alzheimer's Dis. Rev. 1996; 1: 90-98Google Scholar, 10Kim T. Pettingell W.H. Hallmark O.G. Moir R.D. Wasco W. Tanzi R.E. J. Biol. Chem. 1997; 272: 11006-11010Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 13Tomita T. Maruyama K. Saido T.C. Kume H. Shinozaki K. Tokuhiro S. Capell A. Walter J. Grünberg J. Haass C. Iwatsubo T. Obata K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2025-2030Crossref PubMed Scopus (347) Google Scholar). In the present study we have identified proteolytic processing sites in PS1 and PS2 and demonstrate that processing occurs through caspase-type protease(s). We also observed additional, caspase-independent cleavage products suggesting alternative pathways of presenilin processing. We thank D. Jermann and U. Roethlisberger for protein sequencing, H. Doebeli for purification of the (NANP)19 constructs, E. Kitas for peptide synthesis, M. Haenggi, A. Hayes, N. Holzwarth, V. Krumb, and H. P. Kurt for skilled technical assistance, and T. Bartfai for helpful comments and suggestions." @default.
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- W1963923664 title "Presenilins Are Processed by Caspase-type Proteases" @default.
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