Sci. Aging Knowl. Environ., 19 March 2003
Vol. 2003, Issue 11, p. pe7
[DOI: 10.1126/sageke.2003.11.pe7]

PERSPECTIVES

{gamma}-Secretase--Intramembrane Protease with a Complex

Michael S. Wolfe

The author is at the Center for Neurologic Diseases at Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. E-mail: mwolfe{at}rics.bwh.harvard.edu.

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/11/pe7

Key Words: {gamma}-secretase • presenilin • Alzheimer's disease • amyloid {beta} • Notch

Introduction

Hypotheses are generated by envisioning how nature might work. All too often, though, nature surprises us with strange mechanisms that are far more complex than we would have otherwise imagined or believed necessary. Such is the case with {gamma}-secretase, a protease that plays a central role in both embryonic development and the pathogenesis of Alzheimer's disease (AD) (see Honig Case Study). This enzyme hydrolyzes peptide bonds within the transmembrane domain of integral membrane proteins, and how this process occurs in the hydrophobic environment of the lipid bilayer is mysterious. Moreover, {gamma}-secretase has eluded full identification despite intense efforts for over a decade, apparently because this protease is a complex composed of multiple membrane proteins, which can be difficult to study by biochemical means. Recent reports from a number of laboratories, however, have shed substantial light on the mechanism, regulation, and composition of this unusual and complicated enzyme.

{gamma}-Secretase catalyzes the final step in the production of the amyloid {beta} protein (A{beta}) from the amyloid {beta} protein precursor (APP), an integral membrane protein of unknown function closely linked to AD (Fig. 1A) [reviewed in (1) and see "Detangling Alzheimer's Disease"]. After {beta}-secretase releases (sheds) the APP extracellular domain (ectodomain), {gamma}-secretase cleaves the C-terminal remnant in the middle of the transmembrane domain to generate A{beta}. Most A{beta} is 40 residues long (A{beta}40) (Fig. 1B), but a minor 42-residue variant (A{beta}42) is highly prone to self-association and is the major A{beta} species present in cerebral plaques that are characteristic of AD. Certain dominant missense mutations that cause early-onset AD selectively elevate A{beta}42 production (2). These mutations are found in the gene that encodes APP itself and in two genes that encode the multipass membrane proteins presenilin-1 (PS1, also known as PSEN1) and presenilin-2 (PS2, also known as PSEN2). The 50-kD PS protein, which contains eight transmembrane segments (3), is required for {gamma}-secretase activity (4, 5), although a new study from Wilson and colleagues suggests that a portion of A{beta}42 produced in the early steps of the secretory pathway--before APP reaches the plasma membrane--might be created in a PS-independent manner (6).



View larger version (36K):
[in this window]
[in a new window]
 
Fig. 1. Proteolytic processing of APP and Notch and the structure of PS. (A) During the production of A{beta}, the APP ectodomain is first shed by {beta}-secretase to generate a 99-residue membrane fragment (C99). The latter then serves as a substrate for {gamma}-secretase, which cleaves within the transmembrane domain to release A{beta} and the intracellular domain (AICD). Notch is processed in a similar manner after interaction with a cognate ligand: TACE sheds the ectodomain, followed by transmembrane cleavage of the Notch extracellular truncation (NEXT) fragment. This latter {gamma}-secretase-mediated event releases the NICD for nuclear translocation and control of gene expression. Two transmembrane aspartates in the multipass PS are required for both {gamma}-secretase activity and the processing of PS into two pieces (at the arrow). The active site of {gamma}-secretase lies at the interface between these two pieces. (B) Sites of PS/{gamma}-secretase-mediated proteolysis within the transmembrane region of human APP and mouse Notch. The substrates are cleaved at least twice to release A{beta} (or "N{beta}") and AICD (or NICD). Arrows show major sites of cleavage, and arrowheads show minor sites.

 
Presenilin: The Business End of {gamma}-Secretase

PS itself is cut into two pieces, an N-terminal fragment (NTF) and a C-terminal fragment (CTF) (7) (Fig. 2). These two pieces remain associated as a metabolically stable complex, and their formation is tightly regulated by limiting cellular factors (8, 9). These observations suggest that the processed NTF/CTF heterodimer is the functional form of PS. Indeed, coexpression of PS NTF and CTF in worms rescues defects caused by PS loss-of-function mutations (10). Peptide analogs with aspartyl protease-inhibiting motifs block {gamma}-secretase activity (11, 12), and PS contains two conserved aspartates critical for both PS heterodimer formation and {gamma}-secretase activity (13). Taken together, these findings led to the hypothesis that PS undergoes autoproteolysis to become the catalytic component of {gamma}-secretase, a novel intramembrane aspartyl protease (13, 14). Bolstering this idea, {gamma}-secretase inhibitors designed to interact with the enzyme active site bind directly to PS heterodimers (15, 16), and immunoprecipitation with antibodies to PS precipitates {gamma}-secretase activity (17).



View larger version (28K):
[in this window]
[in a new window]
 
Fig. 2. Protein components of the active {gamma}-secretase complex. PS, nicastrin, Aph-1, and Pen-2 assembly leads to PS endoproteolysis into NTF and CTF subunits and to nicastrin maturation into a highly glycosylated (CHO) species. These proteins remain together as the active protease.

 
A very similar or identical {gamma}-secretase activity also cleaves the transmembrane domain of the Notch receptor as part of a signaling pathway critical to cell differentiation during embryogenesis and in adulthood (18). After interaction with cognate protein ligands (for example, Jagged or Delta), Notch undergoes ectodomain shedding catalyzed by tumor necrosis factor-{alpha}-converting enzyme (TACE), which cleaves very close to the transmembrane domain (19, 20) (Fig. 1A). This extracellular shedding event is followed by a second proteolysis within the transmembrane domain that releases the Notch intracellular domain (NICD), which then traverses to the nucleus and interacts with certain transcription factors. This second cut requires PS (4, 5, 21) and its two key aspartates (22-24) and is blocked by {gamma}-secretase inhibitors (21, 24, 25). N-terminal sequencing of the NICD revealed that the proteolysis occurs close to the cytosolic edge of the transmembrane domain (26) (Fig. 1B). In contrast, the {gamma}-secretase cut that releases A{beta} takes place in the very middle of the transmembrane domain of APP, suggesting that different proteases might be responsible for the intramembranous cleavage of APP and Notch. However, this apparent discrepancy has been recently resolved with the finding that the transmembrane domains of these proteins are cleaved at least twice. The intracellular domain of APP (AICD) begins at a site analogous to where the NICD starts (27, 28), and the Notch counterpart of A{beta} results from proteolysis in the middle of the membrane, at sites analogous to the C-terminus of A{beta} (29) (Fig. 1B). These observations have been made not only in transfected cells but also with recombinant APP- and Notch-based substrates using isolated membrane preparations (30). Moreover, the APP and Notch substrates can compete with each other for transmembrane proteolysis both in cells (31) and in membrane preparations (30). Further, immunoprecipitation of PS complexes with specific antibodies precipitates both APP and Notch transmembrane cleaving activities (30). Thus, the evidence suggests that the same enzyme cleaves APP and Notch and is responsible for both cuts within the transmembrane domain.

Protein Partners: Presenilin Has a Complex

Despite the genetic and biochemical evidence that PS is the business end of {gamma}-secretase (that is, it cleaves both APP and Notch), PS clearly does not perform this proteolytic function alone. Overexpression of PS does not lead to either more PS heterodimers or increased {gamma}-secretase activity. PS enters into a high-molecular-mass complex before endoproteolysis, and the resultant NTFs and CTFs remain in this complex (32, 33). Thus, the other interacting proteins in this complex might be the limiting cellular activators of NTF/CTF formation. In search of PS-interacting proteins, Yu and colleagues performed coimmunoprecipitations with antibodies to PS and identified nicastrin, a single-pass membrane protein (34) (Fig. 2). Mutations in nicastrin can affect A{beta} production (34), and knockout of the nicastrin gene in Drosophila eliminates {gamma}-secretase activity with respect to Notch (35-37). In addition, affinity isolation of {gamma}-secretase results in copurification of PS heterodimers and nicastrin in an activity-dependent manner, and immunoprecipitation with antibodies to nicastrin can precipitate {gamma}-secretase activity, suggesting that nicastrin is also a member of the protease complex (38). Recent studies show that a highly glycosylated 150-kD ("mature") form of nicastrin is associated with the active {gamma}-secretase complex, whereas a less glycosylated ("immature") form is not (39). PS deficiencies prevent nicastrin glycosylation and cell surface localization, and "knockdown" of nicastrin levels by RNA interference (RNAi) prevents PS heterodimer formation and blocks {gamma}-secretase activity (39-41). Thus, PS and nicastrin regulate each other's maturation to forms associated with {gamma}-secretase function.

Even still, PS and nicastrin alone do not appear to reconstitute protease activity. Genetic screens in Caenorhabditis elegans have recently revealed two new modifiers of PS function that provide important clues to the regulation of {gamma}-secretase. The two genes, aph-1 and pen-2, encode multipass membrane proteins that cause Notch-like developmental deficiencies when mutated (42, 43). aph-1 encodes a 25-kD protein that is predicted to contain six transmembrane domains, and pen-2 encodes a 10-kD protein that is predicted to pass through the membrane twice (Fig. 2). aph-1 mutations that cause Notch-like defects in worms also prevent nicastrin localization to the cell surface (42). Moreover, down-regulation of aph-1 and pen-2 by RNAi in Drosophila cells prevents Notch and APP proteolysis by {gamma}-secretase, demonstrating that the encoded proteins are required for this protease activity (43). Such RNAi treatment also blocked PS heterodimer formation, showing that these proteins are required for PS maturation to an active complex (43). Similarly, RNAi-mediated down-regulation of pen-2 interferes with the maturation of nicastrin to the highly glycosylated form, and PS and nicastrin are required for proper expression of pen-2 (44).

Biochemical analysis has revealed that the PS, nicastrin, Aph-1, and Pen-2 proteins interact with one another and form a complex (44-47). Immunoprecipitation using antibodies to any of these proteins also precipitates the other three. Moreover, coexpression all four proteins results in substantial increases in PS endoproteolysis and nicastrin maturation (47). That is, the four proteins together enhance the conversion of PS and nicastrin into forms specifically associated with {gamma}-secretase activity. These results suggest that nicastrin, Aph-1, and Pen-2 are the limiting cellular factors that regulate PS NTF/CTF formation. Similarly, PS, Aph-1, and Pen-2 are limiting factors that regulate nicastrin maturation.

Evidence also supports a direct role for these proteins in {gamma}-secretase activity. PS heterodimers, mature nicastrin, Aph-1, and Pen-2 all specifically bind to an immobilized transition-state analog inhibitor of {gamma}-secretase (47). In contrast, these proteins do not associate with a control affinity matrix containing a structurally similar but inactive analog. Further, immunoprecipitation with antibodies to any of these components precipitates {gamma}-secretase activity in solubilized membrane preparations from stably overexpressing cell lines (47). Finally, the stable overexpression of all four components leads to dramatic increases in {gamma}-secretase activity in these same solubilized membrane preparations as compared with membranes from cell lines that do not overexpress one of the components (47). All of these components (PS1, NTF/CTF, mature nicastrin, Aph-1, and Pen-2) copurify through partial purification of {gamma}-secretase activity and comigrate by native polyacrylamide gel electrophoresis. Intriguingly, the molecular mass of these proteins adds up to ~240 kD, the same mass estimated by glycerol velocity gradients. This observation, along with the reconstitution of both presenilinase (the PS autoproteolysis activity) and {gamma}-secretase activity in mammalian cells upon coexpression of these four proteins, suggests that they are the essential components of {gamma}-secretase and is consistent with the idea that PS undergoes autoproteolysis upon assembly with the three other components.

Future Challenges

Definitive proof for this hypothesis will require copurification of these components to homogeneity with retention of {gamma}-secretase or purification of each individually expressed component with subsequent in vitro reconstitution of proteolytic activity. This is now the major challenge for understanding {gamma}-secretase. This protease is a member of a class of intramembrane-cleaving proteases (I-CliPs), which are multipass membrane proteases that hydrolyze the transmembrane regions of their substrates (14, 48). Other I-CliPs include the site 2 protease, a metalloprotease involved in cholesterol metabolism (49), and rhomboid, a serine protease involved in epidermal growth factor receptor signaling (50). No I-CliP has yet been purified to homogeneity, even those suspected to consist of a single uncleaved protein component. However, the yeast protein Ste24p, a metalloprotease with multiple transmembrane segments, has been so purified with retention of activity (51). Although this protease does not process transmembrane domains, its successful purification raises hope that the same can be done for I-CliPs.

Another challenge for this area of research is elucidating the enzyme's mechanism. Both the site of proteolysis in APP and Notch and the location of the two conserved aspartates in PS are within transmembrane domains, suggesting that the active site is embedded in the membrane. This active site must contain a catalytic water molecule and would likely be sequestered in the interior of the protease complex, away from the hydrocarbon chains of the lipid bilayer. The substrate also traverses the membrane and thus can only move within two dimensions. Therefore, a separate substrate docking site, distinct from the active site, would be predicted to be on the outer surface of the protease complex. Indeed, an APP-derived {gamma}-secretase substrate copurifies from a column composed of an immobilized transition-state analog inhibitor, suggesting that the substrate is stalled in the docking site while the inhibitor occupies the active site (38). Other I-CliPs would be expected to work through this same general mechanism. Moreover, the conformation of the substrate transmembrane domain is thought to be helical (11, 52), so the enzyme would have to induce a bending or unwinding of this helix in order to access the amide bond for hydrolysis. How helix breaking might occur is currently unclear, although an explanation has been proffered for the I-CliP S2P (53). In this case, a prior proteolysis is thought to lead to dissociation of two transmembrane domains, triggering a partial helix unwinding by a required arginine-proline sequence.

The identification of Aph-1 and Pen-2 as members of the {gamma}-secretase complex raises the question of whether mutations or other aberrations in the form or level of these proteins can affect A{beta} production and cause AD. How these multipass membrane proteins interact with PS and nicastrin is unclear, as are the biochemical mechanisms by which they, along with nicastrin, allow PS to undergo endoproteolysis to become the catalytic component of the enzyme. No proteins that are closely related to these accessory proteins have been reported so far, let alone those with known biochemical roles that might provide clues. In contrast, a whole family of PS homologs has been identified (54), including signal peptide peptidase (55). Evidence suggests that these PS homologs might contain protease activity by themselves (55), providing simpler model systems to study the mechanism of PS action.

From a biomedical perspective, the question still remains whether {gamma}-secretase is a practical drug target for the treatment of AD. The role of this protease in Notch signaling raises concerns that essential Notch-dependent cell differentiation [for example, T cell maturation (56, 57)] might be compromised by long-term treatment with inhibitors. Moreover, a number of other transmembrane proteins involved in a variety of processes [Erb-B4 (58, 59), E-cadherin (60), LRP (61), CD44 (62), and nectin-1 (63)] have been identified as putative PS-dependent {gamma}-secretase substrates, making it even more difficult to predict the long-term effects of blocking this activity. Nevertheless, complete inhibition may not be required for a therapeutic effect. The recent revelation that transgenic AD mouse models show lower A{beta} production and reduced brain A{beta} plaque loads after administration of a {gamma}-secretase inhibitor for 3 months without obvious toxic effects raises the hope that such agents might be useful therapeutics (64). Despite its complexity, {gamma}-secretase might yet prove to be the key to treating a devastating disease of old age.


March 19, 2003
  1. W. P. Esler, M. S. Wolfe, A portrait of Alzheimer secretases--new features and familiar faces. Science 293, 1449-1454 (2001).[Abstract/Free Full Text]
  2. P. H. St George-Hyslop, Molecular genetics of Alzheimer's disease. Biol. Psychiatry 47, 183-199 (2000).[CrossRef][Medline]
  3. X. Li, I. Greenwald, Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins. Proc. Natl. Acad. Sci. U.S.A. 95, 7109-7114 (1998).[Abstract/Free Full Text]
  4. A. Herreman, L. Serneels, W. Annaert, D. Collen, L. Schoonjans, B. De Strooper, Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat. Cell. Biol. 2, 461-462 (2000).[CrossRef][Medline]
  5. Z. Zhang, P. Nadeau, W. Song, D. Donoviel, M. Yuan, A. Bernstein, B. A. Yankner, Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat. Cell Biol. 2, 463-465 (2000).[CrossRef][Medline]
  6. C. A. Wilson, R. W. Doms, H. Zheng, V. M. Lee, Presenilins are not required for A beta 42 production in the early secretory pathway. Nat. Neurosci. 5, 849-855 (2002).[CrossRef][Medline]
  7. G. Thinakaran, D. R. Borchelt, M. K. Lee, H. H. Slunt, L. Spitzer, G. Kim, T. Ratovitsky, F. Davenport, C. Nordstedt, M. Seeger, J. Hardy, A. I. Levey, S. E. Gandy, N. A. Jenkins, N. G. Copeland, D. L. Price, S. S. Sisodia, Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181-190 (1996).[CrossRef][Medline]
  8. T. Ratovitski, H. H. Slunt, G. Thinakaran, D. L. Price, S. S. Sisodia, D. R. Borchelt, Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J. Biol. Chem. 272, 24536-24541 (1997).[Abstract/Free Full Text]
  9. G. Thinakaran, C. L. Harris, T. Ratovitski, F. Davenport, H. H. Slunt, D. L. Price, D. R. Borchelt, S. S. Sisodia, Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J. Biol. Chem. 272, 28415-28422 (1997).[Abstract/Free Full Text]
  10. D. Levitan, J. Lee, L. Song, R. Manning, G. Wong, E. Parker, L. Zhang, PS1 N- and C-terminal fragments form a complex that functions in APP processing and Notch signaling. Proc. Natl. Acad. Sci. U.S.A. 98, 12186-12190 (2001).[Abstract/Free Full Text]
  11. M. S. Wolfe, W. Xia, C. L. Moore, D. D. Leatherwood, B. Ostaszewski, I. O. Donkor, D. J. Selkoe, Peptidomimetic probes and molecular modeling suggest Alzheimer's {gamma}-secretases are intramembrane-cleaving aspartyl proteases. Biochemistry 38, 4720-4727 (1999).[CrossRef][Medline]
  12. M. S. Shearman, D. Beher, E. E. Clarke, H. D. Lewis, T. Harrison, P. Hunt, A. Nadin, A. L. Smith, G. Stevenson, J. L. Castro. L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity. Biochemistry 39, 8698-8704 (2000).[CrossRef][Medline]
  13. M. S. Wolfe, W. Xia, B. L. Ostaszewski, T. S. Diehl, W. T. Kimberly, D. J. Selkoe, Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and {gamma}-secretase activity. Nature 398, 513-517 (1999).[CrossRef][Medline]
  14. M. S. Wolfe, J. De Los Angeles, D. D. Miller, W. Xia, D. J. Selkoe, Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease. Biochemistry 38, 11223-11230 (1999).[CrossRef][Medline]
  15. Y. M. Li, M. Xu, M. T. Lai, Q. Huang, J. L. Castro, J. DiMuzio-Mower, T. Harrison, C. Lellis, A. Nadin, J. G. Neduvelil, R. B. Register, M. K. Sardana, M. S. Shearman, A. L. Smith, X. P. Shi, K. C. Yin, J. A. Shafer, S. J. Gardell, Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405, 689-694 (2000).[CrossRef][Medline]
  16. W. P. Esler, W. T. Kimberly, B. L. Ostaszewski, T. S. Diehl, C. L. Moore, J.-Y. Tsai, T. Rahmati, W. Xia, D. J. Selkoe, M. S. Wolfe, Transition-state analogue inhibitors of {gamma}-secretase bind directly to presenilin-1. Nat. Cell Biol. 2, 428-434 (2000).[CrossRef][Medline]
  17. Y. M. Li, M. T. Lai, M. Xu, Q. Huang, J. DiMuzio-Mower, M. K. Sardana, X. P. Shi, K. C. Yin, J. A. Shafer, S. J. Gardell, Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc. Natl. Acad. Sci. U.S.A. 97, 6138-6143 (2000).[Abstract/Free Full Text]
  18. R. Kopan, A. Goate, A common enzyme connects notch signaling and Alzheimer's disease. Genes Dev. 14, 2799-2806 (2000).[Free Full Text]
  19. C. Brou, F. Logeat, N. Gupta, C. Bessia, O. LeBail, J. R. Doedens, A. Cumano, P. Roux, R. A. Black, A. Israël, A novel proteolytic cleavage involved in notch signaling: The role of the disintegrin-metalloprotease TACE. Mol. Cell 5, 207-216 (2000).[CrossRef][Medline]
  20. J. S. Mumm, E. H. Schroeter, M. T. Saxena, A. Griesemer, X. Tian, D. J. Pan, W. J. Ray, R. Kopan, A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol. Cell 5, 197-206 (2000).[CrossRef][Medline]
  21. B. De Strooper, W. Annaert, P. Cupers, P. Saftig, K. Craessaerts, J. S. Mumm, E. H. Schroeter, V. Schrijvers, M. S. Wolfe, W. J. Ray, A. Goate, R. Kopan, A presenilin-1-dependent {gamma}-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518-522 (1999).[CrossRef][Medline]
  22. W. J. Ray, M. Yao, J. Mumm, E. H. Schroeter, P. Saftig, M. Wolfe, D. J. Selkoe, R. Kopan, A. M. Goate. Cell surface presenilin-1 participates in the {gamma}-secretase-like proteolysis of Notch. J. Biol. Chem. 274, 36801-36807 (1999).[Abstract/Free Full Text]
  23. H. Steiner, K. Duff, A. Capell, H. Romig, M. G. Grim, S. Lincoln, J. Hardy, X. Yu, M. Picciano, K. Fechteler, M. Citron, R. Kopan, B. Pesold, S. Keck, M. Baader, T. Tomita, T. Iwatsubo, R. Baumeister, C. Haass, A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and notch signaling. J. Biol. Chem. 274, 28669-28673 (1999).[Abstract/Free Full Text]
  24. O. Berezovska, C. Jack, P. McLean, J. C. Aster, C. Hicks, W. Xia, M. S. Wolfe, W. T. Kimberly, G. Weinmaster, D. J. Selkoe, B. T. Hyman, Aspartate mutations in presenilin and {gamma}-secretase inhibitors both impair Notch1 proteolysis and nuclear translocation with relative preservation of Notch1 signaling. J. Neurochem. 75, 583-593 (2000).[CrossRef][Medline]
  25. J. L. Martys-Zage, S. H. Kim, B. Berechid, S. J. Bingham, S. Chu, J. Sklar, J. Nye, S. S. Sisodia, Requirement for presenilin 1 in facilitating lagged 2-mediated endoproteolysis and signaling of notch 1. J. Mol. Neurosci. 15, 189-204 (2000).[CrossRef][Medline]
  26. E. H. Schroeter, J. A. Kisslinger, R. Kopan, Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393, 382-386 (1998).[CrossRef][Medline]
  27. M. Sastre, H. Steiner, K. Fuchs, A. Capell, G. Multhaup, M. M. Condron, D. B. Teplow, C. Haass, Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep. 2, 835-841 (2001).[Abstract/Free Full Text]
  28. C. Yu, S. H. Kim, T. Ikeuchi, H. Xu, L. Gasparini, R. Wang, S. S. Sisodia, Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment gamma. Evidence for distinct mechanisms involved in gamma-secretase processing of the APP and Notch1 transmembrane domains. J. Biol. Chem. 276, 43756-43760 (2001).[Abstract/Free Full Text]
  29. M. Okochi, H. Steiner, A. Fukumori, H. Tanii, T. Tomita, T. Tanaka, T. Iwatsubo, T. Kudo, M. Takeda, C. Haass, Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J. 21, 5408-5416 (2002).[Abstract]
  30. W. T. Kimberly, W. P. Esler, W. Ye, B. L. Ostaszewski, J. Gao, T. S. Diehl, D. J. Selkoe, M. S. Wolfe, Notch and the amyloid precursor protein are cleaved by similar {gamma}-secretase(s). Biochemistry 42, 137-144 (2003).[CrossRef][Medline]
  31. O. Berezovska, C. Jack, A. Deng, N. Gastineau, G. W. Rebeck, B. T. Hyman, Notch1 and amyloid precursor protein are competitive substrates for presenilin 1-dependent {gamma}-secretase cleavage. J. Biol. Chem. 276, 30018-30023 (2001).[Abstract/Free Full Text]
  32. G. Yu, F. Chen, G. Levesque, M. Nishimura, D. M. Zhang, L. Levesque, E. Rogaeva, D. Xu, Y. Liang, M. Duthie, P. H. St George-Hyslop, P. E. Fraser, The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. J. Biol. Chem. 273, 16470-16475 (1998).[Abstract/Free Full Text]
  33. A. Capell, J. Grunberg, B. Pesold, A. Diehlmann, M. Citron, R. Nixon, K. Beyreuther, D. J. Selkoe, C. Haass, The proteolytic fragments of the Alzheimer's disease-associated presenilin-1 form heterodimers and occur as a 100-150-kDa molecular mass complex. J. Biol. Chem. 273, 3205-3211 (1998).[Abstract/Free Full Text]
  34. G. Yu, M. Nishimura, S. Arawaka, D. Levitan, L. Zhang, A. Tandon, Y. Q. Song, E. Rogaeva, F. Chen, T. Kawarai, A. Supala, L. Levesque, H. Yu, D. S. Yang, E. Holmes, P. Milman, Y. Liang, D. M. Zhang, D. H. Xu, C. Sato, E. Rogaev, M. Smith, C. Janus, Y. Zhang, R. Aebersold, L. S. Farrer, S. Sorbi, A. Bruni, P. Fraser, P. St George-Hyslop, Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 407, 48-54 (2000).[CrossRef][Medline]
  35. H. M. Chung, G. Struhl, Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila. Nat. Cell Biol. 3, 1129-1132 (2001).[CrossRef][Medline]
  36. Y. Hu, Y. Ye, M. E. Fortini, Nicastrin is required for gamma-secretase cleavage of the Drosophila Notch receptor. Dev. Cell 2, 69-78 (2002).[CrossRef][Medline]
  37. H. Lopez-Schier, D. St Johnston, Drosophila nicastrin is essential for the intramembranous cleavage of notch. Dev. Cell 2, 79-89 (2002).[CrossRef][Medline]
  38. W. P. Esler, W. T. Kimberly, B. L. Ostaszewski, W. Ye, T. S. Diehl, D. J. Selkoe, M. S. Wolfe, Activity-dependent isolation of the presenilin/{gamma}-secretase complex reveals nicastrin and a {gamma} substrate. Proc. Natl. Acad. Sci. U.S.A. 99, 2720-2725 (2002).[Abstract/Free Full Text]
  39. W. T. Kimberly, M. J. LaVoie, B. L. Ostaszewski, W. Ye, M. S. Wolfe, D. J. Selkoe, Complex N-linked glycosylated nicastrin associates with active gamma-secretase and undergoes tight cellular regulation. J. Biol. Chem. 277, 35113-35117 (2002).[Abstract/Free Full Text]
  40. D. Edbauer, E. Winkler, C. Haass, H. Steiner, Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation. Proc. Natl. Acad. Sci. U.S.A. 99, 8666-8671 (2002).[Abstract/Free Full Text]
  41. D. S. Yang, A. Tandon, F. Chen, G. Yu, H. Yu, S. Arawaka, H. Hasegawa, M. Duthie, S. D. Schmidt, T. V. Ramabhadran, R. A. Nixon, P. M. Mathews, S. E. Gandy, H. T. Mount, P. St George-Hyslop, P. E. Fraser, Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins. J. Biol. Chem. 277, 28135-28142 (2002).[Abstract/Free Full Text]
  42. C. Goutte, M. Tsunozaki, V. A. Hale, J. R. Priess, APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc. Natl. Acad. Sci. U.S.A. 99, 775-779 (2002).[Abstract/Free Full Text]
  43. R. Francis, G. McGrath, J. Zhang, D. A. Ruddy, M. Sym, J. Apfeld, M. Nicoll, M. Maxwell, B. Hai, M. C. Ellis, A. L. Parks, W. Xu, J. Li, M. Gurney, R. L. Myers, C. S. Himes, R. Hiebsch, C. Ruble, J. S. Nye, D. Curtis, aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev. Cell 3, 85-97 (2002).[CrossRef][Medline]
  44. H. Steiner, E. Winkler, D. Edbauer, S. Prokop, G. Basset, A. Yamasaki, M. Kostka, C. Haass, PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. J. Biol. Chem. 277, 39062-39065 (2002).[Abstract/Free Full Text]
  45. S. F. Lee, S. Shah, H. Li, C. Yu, W. Han, G. Yu, Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch. J. Biol. Chem. 277, 45013-45019 (2002).[Abstract/Free Full Text]
  46. Y. Gu, F. Chen, N. Sanjo, T. Kawarai, H. Hasegawa, M. Duthie, W. Li, X. Ruan, A. Luthra, H. T. Mount, A. Tandon, P. E. Fraser, P. St George-Hyslop, 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. 278, 7374-7380 (2003).[Abstract/Free Full Text]
  47. W. T. Kimberly, M. J. LaVoie, W. P. Esler, B. L. Ostaszewski, W. Ye, T. S. Diehl, M. S. Wolfe, D. J. Selkoe, Partial purification and characterization of the {gamma}-secretase complex. Soc. Neurosci. 27 Pt I, Abstract 327.5 (2002).
  48. M. S. Wolfe, D. J. Selkoe, Intramembrane proteases--mixing oil and water. Science 296, 2156-2157 (2002).[Abstract/Free Full Text]
  49. R. B. Rawson, N. G. Zelenski, D. Nijhawan, J. Ye, J. Sakai, M. T. Hasan, T. Y. Chang, M. S. Brown, J. L. Goldstein, Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Mol. Cell 1, 47-57 (1997).[CrossRef][Medline]
  50. S. Urban, J. R. Lee, M. Freeman, Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107, 173-182 (2001).[CrossRef][Medline]
  51. A. Tam, W. K. Schmidt, S. Michaelis, The multispanning membrane protein Ste24p catalyzes CAAX proteolysis and NH2-terminal processing of the yeast a-factor precursor. J. Biol. Chem. 276, 46798-46806 (2001).[Abstract/Free Full Text]
  52. S. F. Lichtenthaler, R. Wang, H. Grimm, S. N. Uljon, C. L. Masters, K. Beyreuther, Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. Proc. Natl. Acad. Sci. U.S.A. 96, 3053-3058 (1999).[Abstract/Free Full Text]
  53. J. Ye, U. P. Dave, N. V. Grishin, J. L. Goldstein, M. S. Brown, Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease. Proc. Natl. Acad. Sci. U.S.A. 97, 5123-5128 (2000).[Abstract/Free Full Text]
  54. C. P. Ponting, M. Hutton, A. Nyborg, M. Baker, K. Jansen, T. E. Golde, Identification of a novel family of presenilin homologues. Hum. Mol. Genet. 11, 1037-1044 (2002).[Abstract/Free Full Text]
  55. A. Weihofen, K. Binns, M. K. Lemberg, K. Ashman, B. Martoglio, Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296, 2215-2218 (2002).[Abstract/Free Full Text]
  56. B. K. Hadland, N. R. Manley, D. Su, G. D. Longmore, C. L. Moore, M. S. Wolfe, E. H. Schroeter, R. Kopan, Gamma-secretase inhibitors repress thymocyte development. Proc. Natl. Acad. Sci. U.S.A. 98, 7487-7491 (2001).[Abstract/Free Full Text]
  57. P. Doerfler, M. S. Shearman, R. M. Perlmutter, Presenilin-dependent gamma-secretase activity modulates thymocyte development. Proc. Natl. Acad. Sci. U.S.A. 98, 9312-9317 (2001).[Abstract/Free Full Text]
  58. C. Y. Ni, M. P. Murphy, T. E. Golde, G. Carpenter, gamma-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294, 2179-2181 (2001).[Abstract/Free Full Text]
  59. H. J. Lee, K. M. Jung, Y. Z. Huang, L. B. Bennett, J. S. Lee, L. Mei, T. W. Kim, Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4. J. Biol. Chem. 277, 6318-6323 (2002).[Abstract/Free Full Text]
  60. P. Marambaud, J. Shioi, G. Serban, A. Georgakopoulos, S. Sarner, V. Nagy, L. Baki, P. Wen, S. Efthimiopoulos, Z. Shao, T. Wisniewski, N. K. Robakis, A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 21, 1948-1956 (2002).[Abstract]
  61. P. May, Y. K. Reddy, J. Herz, Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. J. Biol. Chem. 277, 18736-18743 (2002).[Abstract/Free Full Text]
  62. S. Lammich, M. Okochi, M. Takeda, C. Kaether, A. Capell, A. K. Zimmer, D. Edbauer, J. Walter, H. Steiner, C. Haass, Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide. J. Biol. Chem. 277, 44754-44759 (2002).[Abstract/Free Full Text]
  63. D. Y. Kim, L. A. Ingano, D. M. Kovacs, Nectin-1alpha, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/gamma-secretase-like cleavage. J. Biol. Chem. 277, 49976-49981 (2002).[Abstract/Free Full Text]
  64. P. May, L. Altsteil, M. Bender, L. Boggs, D. Calligaro, K. Fuson, B. Gitter, P. Hyslop, W. Jordan, M. Kallman, W. Li, T. Mabry, R. Mark, B. Ni, J. Nissen, W. Porter, S. Sorgen, Y. Su, J. Audia, H. Dovey, D. Games, V. John, S. Freedman, T. Guido, K. Johnson-Wood, K. Khan, L. Latimer, I. Lieberburg, P. Seubert, E. Thorsett, F. Soriano, D. Schenk, Chronic treatment with a functional gamma-secretase inhibitor reduces Abeta burden and plaque pathology in PDAPP mice. Neurobiol. Aging 23, S133 (2002).
Citation: M. S. Wolfe, {gamma}-Secretase--Intramembrane Protease with a Complex. Sci. SAGE KE 2003, pe7 (19 March 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/11/pe7








Science of Aging Knowledge Environment. ISSN 1539-6150