Processing of β-Secretase by Furin and Other Members of the Proprotein Convertase Family

The amyloid peptide is the main constituent of the amyloid plaques in brain of Alzheimer's disease patients. This peptide is generated from the amyloid precursor protein by two consecutive cleavages. Cleavage at the N terminus is performed by the recently discovered β-secretase (Bace). This aspartyl protease contains a propeptide that has to be removed to obtain mature Bace. Furin and other members of the furin family of prohormone convertases are involved in this process. Surprisingly, β-secretase activity, neither at the classical Asp1 position nor at the Glu11 position of amyloid precursor protein, seems to be controlled by this maturation step. Furthermore, we show that Glu11 cleavage is a function of the expression level of Bace, that it depends on the membrane anchorage of Bace, and that Asp1 cleavage can be followed by Glu11cleavage. Our data suggest that pro-Bace could be active as a β-secretase in the early biosynthetic compartments of the cell and could be involved in the generation of the intracellular pool of the amyloid peptide. We conclude that modulation of the conversion of pro-Bace to mature Bace is not a relevant drug target to treat Alzheimer's disease. The amyloid peptide is the main constituent of the amyloid plaques in brain of Alzheimer's disease patients. This peptide is generated from the amyloid precursor protein by two consecutive cleavages. Cleavage at the N terminus is performed by the recently discovered β-secretase (Bace). This aspartyl protease contains a propeptide that has to be removed to obtain mature Bace. Furin and other members of the furin family of prohormone convertases are involved in this process. Surprisingly, β-secretase activity, neither at the classical Asp1 position nor at the Glu11 position of amyloid precursor protein, seems to be controlled by this maturation step. Furthermore, we show that Glu11 cleavage is a function of the expression level of Bace, that it depends on the membrane anchorage of Bace, and that Asp1 cleavage can be followed by Glu11cleavage. Our data suggest that pro-Bace could be active as a β-secretase in the early biosynthetic compartments of the cell and could be involved in the generation of the intracellular pool of the amyloid peptide. We conclude that modulation of the conversion of pro-Bace to mature Bace is not a relevant drug target to treat Alzheimer's disease. 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Nature. 1999; PubMed Scopus Google to and and The was into This was as to a C-terminal in Bace and The the of Bace the and The the by site the the followed by a and an site The with and in and in which the propeptide cleavage site RLPR↓ was mutated into to the and as that these the by was in a to the C-terminal to the to of the propeptide of Bace, has been A. H. M. H. C. J. S. Multhaup G. C. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). was to the Bace of the members of the proprotein family from The the APP terminus and the of APP been (4De Strooper B. Saftig P. Craessaerts K. Vanderstichele H. Guhde G. Annaert W. Von Figura K. Van Leuven F. Nature. 1998; 391: 387-390Crossref PubMed Scopus (1544) Google Scholar). and and respectively, and from the and was by G. Teplow D.B. R. B. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). from and with a in at followed by to the Craessaerts K. I. G. D. P. B. P. Strooper B. J. 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The protein the the of protein and the the 2 of and with 2 that the protein not the protein in a single of This that the protein the The protein is the Bace the protein is Bace and the is the The large in molecular that the of Bace are is M. Denis P. Y. Mendiaz E.A. Fuller J. Bennett B.D. Kahn S. Ross S. Burgess T. Rogers G. R. Citron M. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of the N terminus of Bace a propeptide of amino in the are and by M. Res. 1999; PubMed Scopus Google Scholar, Biol. 1998; 2: PubMed Scopus Google Scholar, K. Biochem. J. PubMed Scopus Google Scholar). Bace from brain or at R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. Luo Y. Fisher S. Fuller J. Edenson S. Lile J. Jarosinski M.A. Biere A.L. Curran E. Burgess T. Louis J.C. Collins F. Treanor J. Rogers G. Citron M. Science. 1999; 286: 735-741Crossref PubMed Scopus (3271) Google Scholar, 10Sinha S. Anderson J.P. Barbour R. 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PubMed Scopus Google to the of furin in the of Bace and We by the the of protein to be is that wild type Bace of with furin in of the protein the at the of the gel that the propeptide been removed by This was the which not with mature and in to the generated in the presence of furin The of the to mature is with other in in Science. Scholar). This can be by the in the of with the to aspartic conversion that the to with Bace. furin of pro-Bace was to the mature Bace and The in could be by mature Bace not by the propeptide This that this Bace. We that a of pro-Bace was to furin as on the in from which it is that a large of Bace of we conclude that this Bace. this pool is in the early compartments of the it is not which is active in the The of protein that is in on the other the protein that has the and is to furin and are in and is not by the in to Bace Furthermore, protease that this cleavage is performed by a protease not is that the ALPA a site that by a of the identity of this protease and the site of it is that this is recently a single amino acid into the cleavage site of Bace to a This is not in with that the Bace is by a of the the ALPA an cleavage the that Bace and are in with the of the cleavage furin that furin is involved in pro-Bace maturation in other members of the could the cleavage of be other that and and in and Bace of the enzymes was 5 it is that furin was to Furthermore, on was in not in and could be by expression of furin and by expression of the is a protease from the α1-antitrypsin and has been to furin and to a and F. K. G. Y. G. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, S. D. A. M. M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The was performed with Bace of furin in of other of pro-Bace to a as This is to be a cell in the cell the other the data with suggest that furin has a in pro-Bace in of Bace by and with Bace or with furin or or followed by of with or and on or and pro-Bace to the and The an protein of by and with or with furin or and was with and on The position of and is the cleavage and membrane anchorage of Bace β-secretase activity, with Bace, and furin or as in of APP was by in and of C-terminal fragments APP and Aβ or by to and generated by and in of APP in cleavage of APP mainly at the as by the of at the site and by the that of the APP to and on the other which is with data in other cell that β-secretase is and APP is mainly by the in M. Strooper B. Multhaup G. Beyreuther K. J. Neurosci. 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The Glu11 position is to be a cleavage site of Bace R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. Luo Y. Fisher S. Fuller J. Edenson S. Lile J. Jarosinski M.A. Biere A.L. Curran E. Burgess T. Louis J.C. Collins F. Treanor J. Rogers G. Citron M. Science. 1999; 286: 735-741Crossref PubMed Scopus (3271) Google at this position are by of and are in plaques of patients M. Strooper B. Multhaup G. Beyreuther K. J. Neurosci. PubMed Google and We the Glu11 cleavage as a of the Bace in we the of which cleavage of APP at Our to the proteolytic of Bace at position Glu11 as as at position Asp1 and to propeptide is Bace or this of APP was in the of that pro-Bace is an active and or mature Bace is 5 other at can pro-Bace could that mature Bace is in that the of APP. we this we this as of that other in to in in β-secretase cleavage as with Bace or Bace furin in in we that Bace is in the by of a it is of APP This as not propeptide cleavage in the and this protein of Bace expression level on Asp1 and Glu11 cleavage of APP. with of and the of was with 2 of was to this and the and Bace of the was by to and β two of the in the and to the position of the Aβ The as as active as Bace in APP and of cleavage of APP mainly at position Asp1 and The that not at Glu11 in that is in the APP or at the Glu11 which is to the cell membrane the Asp1 site R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. Luo Y. Fisher S. Fuller J. Edenson S. Lile J. Jarosinski M.A. Biere A.L. Curran E. Burgess T. Louis J.C. Collins F. Treanor J. Rogers G. Citron M. Science. 1999; 286: 735-741Crossref PubMed Scopus (3271) Google and that the of Bace is to cleavage at the Glu11 we and that the and maturation of Bace in the M. Denis P. Y. Mendiaz E.A. Fuller J. Bennett B.D. Kahn S. Ross S. Burgess T. Rogers G. R. Citron M. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google A. H. M. H. C. J. S. Multhaup G. C. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). We in that pro-Bace is by furin to mature is in the proteolytic maturation of Bace, other members of the family can of furin We that this maturation is not essential the β-secretase of Bace on APP. 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