Key points are not available for this paper at this time.
γ-Secretase mediates the final proteolytic cleavage, which liberates amyloid β-peptide (Aβ), the major component of senile plaques in the brains of Alzheimer disease patients. Therefore, γ-secretase is a prime target for Aβ-lowering therapeutic strategies. γ-Secretase is a protein complex composed of four different subunits, presenilin (PS), APH-1, nicastrin, and PEN-2, which are most likely present in a 1:1:1:1 stoichiometry. PS harbors the catalytically active site, which is critically required for the aspartyl protease activity of γ-secretase. Moreover, numerous familial Alzheimer disease-associated mutations within the PSs increase the production of the aggregation-prone and neurotoxic 42-amino acid Aβ. Nicastrin may serve as a substrate receptor, although this has recently been challenged. PEN-2 is required to stabilize PS within the γ-secretase complex. No particular function has so far been assigned to APH-1. The four components are sufficient and required for γ-secretase activity. At least six different γ-secretase complexes exist that are composed of different variants of PS and APH-1. All γ-secretase complexes can exert pathological Aβ production. Assembly of the γ-secretase complex occurs within the endoplasmic reticulum, and only fully assembled and functional γ-secretase complexes are transported to the plasma membrane. Structural analysis by electron microscopy and chemical cross-linking reveals a water-containing cavity, which allows intramembrane proteolysis. Specific and highly sensitive γ-secretase inhibitors have been developed; however, they interfere with the physiological function of γ-secretase in Notch signaling and thus cause rather significant side effects in human trials. Modulators of γ-secretase, which selectively affect the production of the pathological 42-amino acid Aβ, do not inhibit Notch signaling. γ-Secretase mediates the final proteolytic cleavage, which liberates amyloid β-peptide (Aβ), the major component of senile plaques in the brains of Alzheimer disease patients. Therefore, γ-secretase is a prime target for Aβ-lowering therapeutic strategies. γ-Secretase is a protein complex composed of four different subunits, presenilin (PS), APH-1, nicastrin, and PEN-2, which are most likely present in a 1:1:1:1 stoichiometry. PS harbors the catalytically active site, which is critically required for the aspartyl protease activity of γ-secretase. Moreover, numerous familial Alzheimer disease-associated mutations within the PSs increase the production of the aggregation-prone and neurotoxic 42-amino acid Aβ. Nicastrin may serve as a substrate receptor, although this has recently been challenged. PEN-2 is required to stabilize PS within the γ-secretase complex. No particular function has so far been assigned to APH-1. The four components are sufficient and required for γ-secretase activity. At least six different γ-secretase complexes exist that are composed of different variants of PS and APH-1. All γ-secretase complexes can exert pathological Aβ production. Assembly of the γ-secretase complex occurs within the endoplasmic reticulum, and only fully assembled and functional γ-secretase complexes are transported to the plasma membrane. Structural analysis by electron microscopy and chemical cross-linking reveals a water-containing cavity, which allows intramembrane proteolysis. Specific and highly sensitive γ-secretase inhibitors have been developed; however, they interfere with the physiological function of γ-secretase in Notch signaling and thus cause rather significant side effects in human trials. Modulators of γ-secretase, which selectively affect the production of the pathological 42-amino acid Aβ, do not inhibit Notch signaling. AD 3The abbreviations used are: AD, Alzheimer disease; Aβ, amyloid β-peptide; APP, β-amyloid precursor protein; CTF, C-terminal fragment; TMD, transmembrane domain; ICD, intracellular domain; PS, presenilin; SPP, signal peptide peptidase; SPPL, SPP-like; FAD, familial AD; NCT, nicastrin; GSI, γ-secretase inhibitor. is the most frequent dementia in the world, affecting millions of people. The amyloid cascade hypothesis, which describes a number of consecutive steps finally leading to synapse dysfunction, synapse loss, and neuronal cell death, is based on the cellular production of Aβ, which initiates the deadly cascade (1Hardy J. Selkoe D.J. Science. 2002; 297: 353-356Crossref PubMed Scopus (11361) Google Scholar). Aβ metabolism is in the center of intense research because Aβ lowering strategies may finally lead to therapeutic treatment or even prevention of AD. The highly amyloidogenic Aβ is released from its precursor, APP, by two sequential proteolytic cleavages mediated by β- and γ-secretases. β-Secretase (BACE1 (β-site APP-cleaving enzyme 1)) (reviewed by Cole and Vassar (64Cole S.L. Vassar R. J. Biol. Chem. 2008; 283: 29621-29625Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar) in the second article of this minireview series) removes the bulk of the ectodomain of APP and leaves behind a small membrane-retained CTF (Fig. 1A). Whereas β-secretase cleavage is mediated by a rather conventional aspartyl protease, the second cut is mediated by an unusual protease, γ-secretase. With the identification of APP (2Kang J. Lemaire H.G. Unterbeck A. Salbaum J.M. Masters C.L. Grzeschik K.H. Multhaup G. Beyreuther K. Muller-Hill B. Nature. 1987; 325: 733-736Crossref PubMed Scopus (4060) Google Scholar), it became apparent that Aβ has to be liberated from the membrane probably by an intramembrane cleavage event (Fig. 1, A and B). However, in such a hydrophobic environment, water molecules are either absent or at least very rare. Therefore, biochemists did not believe in physiologically occurring intramembrane cleavage of peptide bonds, and in fact, AD researchers assumed for a long time that Aβ could be generated only upon membrane destruction and subsequent release of the precursor into the brain parenchyma, where conventional proteases would then have access. However, three laboratories independently discovered that Aβ is physiologically produced throughout life by a cellular pathway that must involve intramembrane proteolysis because membrane damage and release of the precursor could be clearly excluded (3Busciglio J. Gabuzda D.H. Matsudaira P. Yankner B.A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 2092-2096Crossref PubMed Scopus (532) Google Scholar, 4Shoji M. Golde T.E. Ghiso J. Cheung T.T. Estus S. Shaffer L.M. Cai X.D. McKay D.M. Tintner R. Frangione B. Younkin S.G. Science. 1992; 258: 126-129Crossref PubMed Scopus (1334) Google Scholar, 5Haass C. Schlossmacher M.G. Hung A.Y. Vigo-Pelfrey C. Mellon A. Ostaszewski B.L. Lieberburg I. Koo E.H. Schenk D. Teplow D.B. Selkoe D.J. Nature. 1992; 359: 322-325Crossref PubMed Scopus (1776) Google Scholar). Thus, APP processing turned out to be the first example not only for intramembrane cleavage but also for a cellular pathway now termed regulated intramembrane proteolysis. Regulated intramembrane proteolysis describes the sequential processing of an increasing number of single-pass transmembrane proteins, which in some cases is coupled to nuclear signaling (6Brown M.S. Ye J. Rawson R.B. Goldstein J.L. Cell. 2000; 100: 391-398Abstract Full Text Full Text PDF PubMed Scopus (1158) Google Scholar). In the first step, shedding removes large parts of the substrate's ectodomain. In many cases, the sheddases belong to the family of the ADAM (a disintegrin and metalloprotease) proteases. Other sheddases such as BACE1 may cleave a more restricted panel of substrates (see review article by Cole and Vassar (64Cole S.L. Vassar R. J. Biol. Chem. 2008; 283: 29621-29625Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar)). The remaining stub is then cleaved within its TMD by intramembrane-cleaving proteases termed I-CLiPs (7Wolfe M.S. Kopan R. Science. 2004; 305: 1119-1123Crossref PubMed Scopus (311) Google Scholar). In several cases, it is now known that the intramembrane cleavage results in the release of an ICD, which is involved in nuclear signaling and transcriptional regulation (7Wolfe M.S. Kopan R. Science. 2004; 305: 1119-1123Crossref PubMed Scopus (311) Google Scholar, 8Haass C. EMBO J. 2004; 23: 483-488Crossref PubMed Scopus (494) Google Scholar). However, there is strong evidence that at least the intramembrane-cleaving γ-secretase may also fulfill a second and probably major function. In that case, γ-secretase seems to be required for the efficient destruction of membrane-retained protein fragments. This activity has been referred to as the “membrane-proteasome” function of γ-secretase (9Kopan R. Ilagan M.X. Nat. Rev. Mol. Cell Biol. 2004; 5: 499-504Crossref PubMed Scopus (504) Google Scholar). Whereas γ-secretase takes apart membrane stubs, the final degradation of the ICD (see for example, Ref. 10Edbauer D. Willem M. Lammich S. Steiner H. Haass C. J. Biol. Chem. 2002; 277: 13389-13393Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar) and the secreted peptides (see for example, Ref. 11Iwata N. Tsubuki S. Takaki Y. Shirotani K. Lu B. Gerard N.P. Gerard C. Hama E. Lee H.J. Saido T.C. Science. 2001; 292: 1550-1552Crossref PubMed Scopus (860) Google Scholar) is performed by other proteases. γ-Secretase is the founding member of the intramembrane-cleaving aspartyl proteases. Although γ-secretase was the first proposed protease activity, which mediates intramembrane cleavage, its identification took a long time, and structural data are still available only to a very limited extent (12Lazarov V.K. Fraering P.C. Ye W. Wolfe M.S. Selkoe D.J. Li H. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 6889-6894Crossref PubMed Scopus (151) Google Scholar). There is a good reason for this “slowed” progress as compared with other intramembrane-cleaving proteases because γ-secretase turned out to be a complicated complex composed of four essential subunits (13Edbauer D. Winkler E. Regula J.T. Pesold B. Steiner H. Haass C. Nat. Cell Biol. 2003; 5: 486-488Crossref PubMed Scopus (790) Google Scholar), the precise interactions of which are technically very difficult to investigate. One of the subunits, PS, contains the two catalytically active aspartate residues (14Wolfe M.S. Xia W. Ostaszewski B.L. Diehl T.S. Kimberly W.T. Selkoe D.J. Nature. 1999; 398: 513-517Crossref PubMed Scopus (1716) Google Scholar), which are located within TMD6 and TMD7 (Fig. 1A). The N-terminal catalytically active site of PS is embedded in a conserved YD motif, whereas the C-terminal active-site domain contains the equally conserved GXGD motif (15Steiner H. Kostka M. Romig H. Basset G. Pesold B. Hardy J. Capell A. Meyn L. Grim M.G. Baumeister R. Fechteler K. Haass C. Nat. Cell Biol. 2000; 2: 848-851Crossref PubMed Scopus (256) Google Scholar), which now serves as the family-characterizing name of the GXGD-type aspartyl proteases (16Haass C. Steiner H. Trends Cell Biol. 2002; 12: 556-562Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar). Besides γ-secretase/PS, two families of related proteases, which also belong to the GXGD-type aspartyl proteases, have been identified. These include the procaryotic type 4 prepilin peptidases and SPP, as well as the SPP homologs, the SPPL proteases (see also the related data on SPP/SPPL by Fluhrer et al. 4R. Fluhrer, H. Steiner, and C. Haass, submitted for publication. ). The catalytic subunit of γ-secretase, PS, is the best studied GXGD-type I-CLiP (17Steiner H. Curr. Alzheimer Res. 2008; 5: 147-157Crossref PubMed Scopus (34) Google Scholar) and represents the prototype of this novel class of aspartyl proteases (16Haass C. Steiner H. Trends Cell Biol. 2002; 12: 556-562Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar). PS is a polytopic membrane protein consisting of nine TMDs and is cleaved into an N-terminal and C-terminal (Fig. G. Lee L. G. C. M. Hardy J. Full Text Full Text PDF PubMed Scopus Google Scholar). This cleavage occurs within the large TMD6 and TMD7 within a hydrophobic domain that is to into the membrane and is very likely an event (13Edbauer D. Winkler E. Regula J.T. Pesold B. Steiner H. Haass C. Nat. Cell Biol. 2003; 5: 486-488Crossref PubMed Scopus (790) Google Scholar), although this has not been is not an for γ-secretase activity H. Romig H. Pesold B. U. M. M. H. H. Haass C. 1999; PubMed Scopus Google Scholar) as (14Wolfe M.S. Xia W. Ostaszewski B.L. Diehl T.S. Kimberly W.T. Selkoe D.J. Nature. 1999; 398: 513-517Crossref PubMed Scopus (1716) Google Scholar), but it may rather be required to of the two active-site in TMD6 and TMD7 of PS was as a protein to AD by the that mutations in the two of PS in and are with in 8Haass C. EMBO J. 2004; 23: 483-488Crossref PubMed Scopus (494) Google and H. Curr. Alzheimer Res. 2008; 5: 147-157Crossref PubMed Scopus (34) Google Scholar). 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Although the is so far in a increase of γ-secretase cleavage at the affecting the This of of cleavage at the has also been for S. H. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), γ-secretase However, it also be more has been in the degradation of secreted Aβ and may thus not be involved in γ-secretase activity H. Lee S. P. Y. N. Lee Saido T.C. Li G. J. Biol. Chem. 2008; 283: Full Text Full Text PDF PubMed Scopus Google Scholar). mutations in the domain of APP have recently been to affect cleavage affecting γ-secretase cleavage at the Schenk D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, there are also affecting cleavage within the are required to the of of γ-secretase research the and for the first time to and sensitive which in the long may out to the to an
Steiner et al. (Thu,) studied this question.