The γ-secretase complex: Membrane-embedded proteolytic ensemble

Biochemistry

Volumn 45, Issue 26, 2006, Pages 7931-7939

  Wolfe, Michael S ^a  

^a Brigham and Women's Hospital Center for Neurologic Diseases   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL MEMBRANES; DISEASE CONTROL; HYDROLYSIS; LIPIDS; SUBSTRATES;

ALLOSTERIC REGULATION; ALZHEIMER'S DISEASE THERAPEUTICS; MEMBRANE PROTEINS; MEMBRANE-ASSOCIATED FRAGMENTS;

ENZYMES;

AMYLOID BETA PROTEIN[1-42]; ANTERIOR PHARYNX DEFECTIVE 1 PROTEIN; ASPARTIC ACID; FLURBIPROFEN; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; IBUPROFEN; IMATINIB; INDOMETACIN; MEMBRANE PROTEIN; NICASTRIN; NONSTEROID ANTIINFLAMMATORY AGENT; NOTCH RECEPTOR; PRESENILIN 1; PRESENILIN 2; PROTEIN PEN2; SULINDAC SULFIDE; UNCLASSIFIED DRUG; WATER;

ALLOSTERISM; ALZHEIMER DISEASE; AMINO TERMINAL SEQUENCE; ARTICLE; CLINICAL TRIAL; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME SUBSTRATE COMPLEX; HUMAN; HYDROLYSIS; LIPID BILAYER; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN ASSEMBLY; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN PROCESSING; SIGNAL TRANSDUCTION; STRUCTURE ANALYSIS;

AMYLOID BETA-PROTEIN PRECURSOR; AMYLOID PRECURSOR PROTEIN SECRETASES; CELL MEMBRANE; ENDOPEPTIDASES; IMAGE PROCESSING, COMPUTER-ASSISTED; MEMBRANE PROTEINS; MODELS, MOLECULAR; PROTEIN PROCESSING, POST-TRANSLATIONAL; RECEPTORS, NOTCH;

EID: 33745614108     PISSN: 00062960     EISSN: None     Source Type: Journal    
DOI: 10.1021/bi060799c     Document Type: Article

References (104)

1. Glenner, G. G., and Wong, C. W. (1984) Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochem. Biophys. Res. Commun. 120, 885-90.
2. Selkoe, D. J. (2001) Alzheimer's disease: Genes, proteins, and therapy, Physiol. Rev. 81, 741-66.
3. Hardy, J. (1997) Amyloid, the presenilins and Alzheimer's disease, Trends Neurosci. 20, 154-9.
4. Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., and Sejkoe, D. J. (1992) Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production, Nature 360, 672-4.
5. Cai, X. D., Golde, T. E., and Younkin, S. G. (1993) Release of excess amyloid β protein from a mutant amyloid β protein precursor, Science 259, 514-6.
6. Suzuki, N., Cheung, T. T., Cai, X. D., Odaka, A., Otvos, L., Jr., Eckman, C., Golde, T. E., and Younkin, S. G. (1994) An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP717) mutants, Science 264, 1336-40.
7. Roher, A. E., Lowenson, J. D., Clarke, S., Woods, A. S., Cotter, R. J., Cowing, E., and Ball, M. J. (1993) β-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: Implications for the pathology of Alzheimer disease, Proc. Natl. Acad. Sci. U.S.A. 90, 10836-40.
8. Iwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N., and Ihara, Y. (1994) Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific A β monoclonals: Evidence that an initially deposited species is Aβ42(43), Neuron 13, 45-53.
9. Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease, Nature 375, 754-60.
10. Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C. E., Jondro, P. D., Schmidt, S. D., Wang, K., et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus, Science 269, 973-7.
11. Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., et ai. (1995) 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 376, 775-8.
12. L'Hernault, S. W., and Arduengo, P. M. (1992) Mutation of a putative sperm membrane protein in Caenorhabditis elegans prevents sperm differentiation but not its associated meiotic divisions, J. Cell Biol. 119, 55-68.
13. Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Mutton, M., Kukull, W., Larson, E., Levy-Lahad, E., Viitanen, M., Peskind, E., Poorkaj, P., Schellenberg, G., Tanzi, R., Wasco, W., Lannfelt, L., Selkoe, D., and Younkin, S. (1996) Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nat. Med. 2, 864-70.
14. Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C. M., Perez-tur, J., Mutton, M., Buee, L., Harigaya, Y., Yager, D., Morgan, D., Gordon, M. N., Holcomb, L., Refolo, L., Zenk, B., Hardy, J., and Younkin, S. (1996) Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1, Nature 383, 710-3.
15. Lemere, C. A., Lopera, F., Kosik, K. S., Lendon, C. L., Ossa, J., Saido, T. C., Yamaguchi, H., Ruiz, A., Martinez, A., Madrigal, L., Hincapie, L., Arango, J. C., Anthony, D. C., Koo, E. H., Goate, A. M., Selkoe, D. J., and Arango, J. C. (1996) The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology, Nat. Med. 2, 1146-50.
16. Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-Wood, K., Lee, M., Seubert, P., Davis, A., Kholodenko, D., Motter, R., Sherrington, R., Perry, B., Yao, H., Strome, R., Lieberburg, I., Rommens, J., Kim, S., Schenk, D., Fraser, P., St George Hyslop, P., and Selkoe, D. J. (1997) Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice, Nat. Med. 3, 67-72.
17. Tanzi, R. E., and Bertram, L. (2005) Twenty years of the Alzheimer's disease amyloid hypothesis: A genetic perspective, Cell 120, 545-55.
18. De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., Von Figura, K., and Van Leuven, F. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein, Nature 391, 387-90.
19. Artavanis-Tsakonas, S., Rand, M. D., and Lake, R. J. (1999) Notch signaling: Cell fate control and signal integration in development, Science 284, 770-6.
20. Levitan, D., and Greenwald, I. (1995) Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene, Nature 377, 351-4.
21. Schroeter, E. H., Kisslinger, J. A., and Kopan, R. (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain, Nature 393, 382-6.
22. Wong, P. C., Zheng, H., Chen, H., Becher, M. W., Sirinathsinghji, D. J., Trumbauer, M. E., Chen, H. Y., Price, D. L., Van der Ploeg, L. H., and Sisodia, S. S. (1997) Presenilin 1 is required for Notch 1 and Dili expression in the paraxial mesoderm, Nature 387, 288-92.
23. Shen, J., Bronson, R. T., Chen, D. F., Xia, W., Selkoe, D. J., and Tonegawa, S. (1997) Skeletal and CNS defects in presenilin-1-deficient mice, Cell 89, 629-39.
24. De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J. S., Schroeter, E. H., Schrijvers, V., Wolfe, M. S., Ray, W. J., Goate, A., and Kopan, R. (1999) A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain, Nature 398, 518-22.
25. Kim, J., and Schekman, R. (2004) The ins and outs of presenilin 1 membrane topology, Proc. Natl. Acad. Sci. U.S.A. 101, 905-6.
26. Li, X., and Greenwald, I. (1996) Membrane topology of the C. elegans SEL-12 presenilin, Neuron 17, 1015-21.
27. Li, X., and Greenwald, I. (1998) Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins, Proc. Natl. Acad. Sci. U.S.A. 95, 7109-14.
28. Doan, A., Thinakaran, G., Borchelt, D. R., Slunt, H. H., Ratovitsky, T., Podlisny, M., Selkoe, D. J., Seeger, M., Candy, S. E., Price, D. L., and Sisodia, S. S. (1996) Protein topology of presenilin 1, Neuron 17, 1023-30.
29. Laudon, H., Hansson, E. M., Melen, K., Bergman, A., Farmery, M. R., Winblad, B., Lendahl, U., von Heijne, G., and Naslund, J. (2005) A nine-transmembrane domain topology for presenilin 1, J. Biol. Chem. 280, 35352-60.
30. Oh, Y. S., and Turner, R. J. (2005) Topology of the C-terminal fragment of human presenilin 1, Biochemistry 44, 11821-8.
31. Thinakaran, 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., and Sisodia, S. S. (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo, Neuron 17, 181-90.
32. Ratovitski, T., Slunt, H. H., Thinakaran, G., Price, D. L., Sisodia, S. S., and Borchelt, D. R. (1997) Endoproteolytic processing and stabilization of wild-type and mutant presenilin, J. Biol. Chem. 272, 24536-41.
33. Thinakaran, G., Harris, C. L., Ratovitski, T., Davenport, F., Slunt, H. H., Price, D. L., Borchelt, D. R., and Sisodia, S. S. (1997) Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors, J. Biol. Chem. 272, 28415-22.
34. Wolfe, M. S., Xia, W., Moore, C. L., Leatherwood, D. D., Ostaszewski, B., Donkor, I. O., and Selkoe, D. J. (1999) Peptidomimetic probes and molecular modeling suggest Alzheimer's γ-secretases are intramembrane-cleaving aspartyl proteases, Biochemistry 38, 4720-7.
35. Shearman, M. S., Beher, D., Clarke, E. E., Lewis, H. D., Harrison, T., Hunt, P., Nadin, A., Smith, A. L., Stevenson, G., and Castro, J. L. (2000) L-685,458, an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid β-Protein Precursor γ-Secretase Activity, Biochemistry 39, 8698-704.
36. Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., and Selkoe, D. J. (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity, Nature 398, 513-7.
37. Wolfe, M. S., De Los Angeles, J., Miller, D. D., Xia, W., and Selkoe, D. J. (1999) Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease, Biochemistry 38, 11223-30.
38. Li, Y. M., Xu, M., Lai, M. T., Huang, Q., Castro, J. L., DiMuzio-Mower, J., Harrison, T., Lellis, C., Nadin, A., Neduvelil, J. G., Register, R. B., Sardana, M. K., Shearman, M. S., Smith, A. L., Shi, X. P., Yin, K. C., Shafer, J. A., and Gardell, S. J. (2000) Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1, Nature 405, 689-94.
39. Esler, W. P., Kimberly, W. T., Ostaszewski, B. L., Diehl, T. S., Moore, C. L., Tsai, J.-Y., Rahmati, T., Xia, W., Selkoe, D. J., and Wolfe, M. S. (2000) Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1, Nat. Cell Biol. 2, 428-34.
40. Capell, A., Grunberg, J., Pesold, B., Diehlmann, A., Citron, M., Nixon, R., Beyreuther, K., Selkoe, D. J., and Haass, C. (1998) 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, 3205-11.
41. Yu, G., Chen, F., Levesque, G., Nishimura, M., Zhang, D. M., Levesque, L., Rogaeva, E., Xu, D., Liang, Y., Duthie, M., St George-Hyslop, P. H., and Fraser, P. E. (1998) The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains β-catenin, J. Biol. Chem. 273, 16470-5.
42. Weihofen, A., Binns, K., Lemberg, M. K., Ashman, K., and Martoglio, B. (2002) Identification of signal peptide peptidase, a presenilin-type aspartic protease, Science 296, 2215-8.
43. Kang, D., Soriano, S., Xia, X., Eberhart, C., De Strooper, B., Zheng, H., and Koo, E. (2002) Presenilin Couples the Paired Phosphorylation of β-Catenin Independent of Axin. Implications for β-Catenin Activation in Tumorigenesis, Cell 110, 751.
44. Baki, L., Shioi, J., Wen, P., Shao, Z., Schwarzman, A., Gama-Sosa, M., Neve, R., and Robakis, N. K. (2004) PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: Effects of FAD mutations, EMBO J. 23, 2586-96.
45. Huppert, S. S., Ilagan, M. X., De Strooper, B., and Kopan, R. (2005) Analysis of Notch function in presomitic mesoderm suggests a γ-secretase-independent role for presenilins in somite differentiation, Dev. Cell 8, 677-88.
46. Song, W., Nadeau, P., Yuan, M., Yang, X., Shen, J., and Yankner, B. A. (1999) Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations, Proc. Natl. Acad. Sci. U.S.A. 96, 6959-63.
47. Bentahir, M., Nyabi, O., Verhamme, J., Tolia, A., Horre, K., Wiltfang, J., Esselmann, H., and De Strooper, B. (2006) Presenilin clinical mutations can affect γ-secretase activity by different mechanisms, J. Neureuchem. 96, 732-42.
48. Weidemann, A., Eggert, S., Reinhard, F. B., Vogel, M., Paliga, K., Baier, G., Masters, C. L., Beyreuther, K., and Evin, G. (2002) A Novel var epsilon-Cleavage within the Transmembrane Domain of the Alzheimer Amyloid Precursor Protein Demonstrates Homology with Notch Processing, Biochemistry 41, 2825-35.
49. Sato, T., Dohmae, N., Qi, Y., Kakuda, N., Misonou, H., Mitsumori, R., Maruyama, H., Koo, E. H., Haass, C., Takio, K., Morishima-Kawashima, M., Ishiura, S., and Ihara, Y. (2003) Potential link between amyloid β-protein 42 and C-terminal fragment γ49-99 of β-amyloid precursor protein, J. Biol. Chem. 278, 24294-301.
50. Yu, G., Nishimura, M., Arawaka, S., Levitan, D., Zhang, L., Tandon, A., Song, Y. Q., Rogaeva, E., Chen, F., Kawarai, T., Supala, A., Levesque, L., Yu, H., Yang, D. S., Holmes, E., Milman, P., Liang, Y., Zhang, D. M., Xu, D. H., Sato, C., Rogaev, E., Smith, M., Janus, C., Zhang, Y., Aebersold, R., Farrer, L. S., Sorbi, S., Bruni, A., Fraser, P., and St George-Hyslop, P. (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing, Nature 407, 48-54.
51. Esler, W. P., Kimberly, W. T., Ostaszewski, B. L., Ye, W., Diehl, T. S., Selkoe, D. J., and Wolfe, M. S. (2002) Activity-dependent isolation of the presenilin/γ-secretase complex reveals nicastrin and a γ substrate, Proc. Natl. Acad. Sci. U.S.A. 99, 2720-5.
52. Edbauer, D., Winkler, E., Haass, C., and Steiner, H. (2002) Presenilin and nicastrin regulate each other and determine amyloid β-peptide production via complex formation, Proc. Natl. Acad. Sci. U.S.A. 99, 8666-71.
53. Arawaka, S., Hasegawa, H., Tandon, A., Janus, C., Chen, F., Yu, G., Kikuchi, K., Koyama, S., Kato, T., Fraser, P. E., and St George-Hyslop, P. (2002) The levels of mature glycosylated nicastrin are regulated and correlate with γ-secretase processing of amyloid β-precursor protein, J. Neurochem. 83, 1065-71.
54. Kimberly, W. T., LaVoie, M. J., Ostaszewski, B. L., Ye, W., Wolfe, M. S., and Selkoe, D. J. (2002) Complex N-linked glycosylated nicastrin associates with active γ-secretase and undergoes tight cellular regulation, J. Biol. Chem. 277, 35113-7.
55. Leem, J. Y., Vijayan, S., Han, P., Cai, D., Machura, M., Lopes, K. O., Veselits, M. L., Xu, H., and Thinakaran, G. (2002) Presenilin 1 is required for maturation and cell surface accumulation of nicastrin, J. Biol. Chem. 277, 19236-40.
56. Tomita, T., Katayama, R., Takikawa, R., and Iwatsubo, T. (2002) Complex N-glycosylated form of nicastrin is stabilized and selectively bound to presenilin fragments, FEBS Lett. 520, 117-21.
57. Goutte, C., Hepler, W., Mickey, K. M., and Priess, J. R. (2000) aph-2 encodes a novel extracellular protein required for GLP-1-mediated signaling, Development 127, 2481-92.
58. Li, T., Ma, G., Cai, H., Price, D. L., and Wong, P. C. (2003) Nicastrin is required for assembly of presenilin/γ-secretase complexes to mediate Notch signaling and for processing and trafficking of β-amyloid precursor protein in mammals, J. Neurosci. 23, 3272-7.
59. Francis, R., McGrath, G., Zhang, J., Ruddy, D. A., Sym, M., Apfeld, J., Nicoll, M., Maxwell, M., Hai, B., Ellis, M. C., Parks, A. L., Xu, W., Li, J., Gurney, M., Myers, R. L., Himes, C. S., Hiebsch, R., Ruble, C., Nye, J. S., and Curtis, D. (2002) aph-1 and pen-2 are required for Notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation, Dev. Cell 3, 85-97.
60. Takasugi, N., Tomita, T., Hayashi, I., Tsuruoka, M., Niimura, M., Takahashi, Y., Thinakaran, G., and Iwatsubo, T. (2003) The role of presenilin cofactors in the γ-secretase complex, Nature 422, 438-41.
61. Kimberly, W. T., LaVoie, M. J., Ostaszewski, B. L., Ye, W., Wolfe, M. S., and Selkoe, D. J. (2003) γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2, Proc. Natl. Acad. Sci. U.S.A. 100, 6382-7.
62. Edbauer, D., Winkler, E., Regula, J. T., Pesold, B., Steiner, H., and Haass, C. (2003) Reconstitution of γ-secretase activity, Nat. Cell Biol. 5, 486-8.
63. Fraering, P. C., Ye, W., Strub, J. M., Dolios, G., LaVoie, M. J., Ostaszewski, B. L., Van Dorsselaer, A., Wang, R., Selkoe, D. J., and Wolfe, M. S. (2004) Purification and Characterization of the Human γ-Secretase Complex, Biochemistry 43, 9774-89.
64. Shah, S., Lee, S. F., Tabuchi, K., Hao, Y. H., Yu, C., LaPlant, Q., Ball, H., Dann, C. E., III, Sudhof, T., and Yu, G. (2005) Nicastrin functions as a γ-secretase-substrate receptor, Cell 122, 435-47.
65. Zhou, S., Zhou, H., Walian, P. J., and Jap, B. K. (2005) CD147 is a regulatory subunit of the γ-secretase complex in Alzheimer's disease amyloid β-peptide production, Proc. Natl. Acad. Sci. U.S.A. 102, 7499-504.
66. Lazarov, V. K., Fraering, P. C., Ye, W., Wolfe, M. S., Selkoe, D. J., and Li, H. (2006) Electron microscopic structure of purified, active γ-secretase reveals an aqueous intramembrane chamber and two pores, Proc. Natl. Acad. Sci. U.S.A. 103, 6889-94.
67. Schroeter, E. H., Ilagan, M. X., Brunkan, A. L., Hecimovic, S., Li, Y. M., Xu, M., Lewis, H. D., Saxena, M. T., De Strooper, B., Coonrod, A., Tomita, T., Iwatsubo, T., Moore, C. L., Goate, A., Wolfe, M. S., Shearman, M., and Kopan, R. (2003) A presenilin dimer at the core of the γ-secretase enzyme: Insights from parallel analysis of Notch 1 and APP proteolysis, Proc. Natl. Acad. Sci. U.S.A. 100, 13075-80.
68. Hebert, S. S., Godin, C., Tomiyama, T., Mori, H., and Levesque, G. (2003) Dimerization of presenilin-1 in vivo: Suggestion of novel regulatory mechanisms leading to higher order complexes, Biochem. Biophys. Res. Commun. 301, 119-26.
69. Cervantes, S., Saura, C. A., Pomares, E., Gonzalez-Duarte, R., and Marfany, G. (2004) Functional implications of the presenilin dimerization. Reconstitution of γ-secretase activity by assembly of a catalytic site at the dimer interface of two catalytically inactive presenilins, J. Biol. Chem. 279, 36519-29.
70. Nyborg, A. C., Kornilova, A. Y., Jansen, K., Ladd, T. B., Wolfe, M. S., and Golde, T. E. (2004) Signal peptide peptidase forms a homodimer that is labeled by an active site-directed γ-secretase inhibitor, J. Biol. Chem. 279, 15153-60.
71. Kopan, R., and Ilagan, M. X. (2004) γ-Secretase: Proteasome of the membrane? Nat. Rev. Mol. Cell Biol. 5, 499-504.
72. Lai, M. T., Chen, E., Crouthamel, M. C., DiMuzio-Mower, J., Xu, M., Huang, Q., Price, E., Register, R. B., Shi, X. P., Donoviel, D. B., Bernstein, A., Hazuda, D., Gardell, S. J., and Li, Y. M. (2003) Presenilin-1 and presenilin-2 exhibit distinct yet overlapping γ-secretase activities, J. Biol. Chem. 278, 22475-81.
73. Gu, Y., Chen, F., Sanjo, N., Kawarai, T., Hasegawa, H., Duthie, M., Li, W., Ruan, X., Luthra, A., Mount, H. T., Tandon, A., Fraser, P. E., and St George-Hyslop, P. (2002) 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, 7374-80.
74. LaVoie, M. J., Fraering, P. C., Ostaszewski, B. L., Ye, W., Kimberly, W. T., Wolfe, M. S., and Selkoe, D. J. (2003) Assembly of the γ-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin, J. Biol. Chem. 278, 37213-22.
75. Luo, W. J., Wang, H., Li, H., Kim, B. S., Shah, S., Lee, H. J., Thinakaran, G., Kim, T. W., Yu, G., and Xu, H. (2003) PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1, J. Biol. Chem. 278, 7850-4.
76. Fraering, P. C., LaVoie, M. J., Ye, W., Ostaszewski, B. L., Kimberly, W. T., Selkoe, D. J., and Wolfe, M. S. (2004) Detergent-dependent dissociation of active γ-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex, Biochemistry 43, 323-33.
77. Watanabe, N., Tomita, T., Sato, C., Kitamura, T., Morohashi, Y., and Iwatsubo, T. (2005) Pen-2 is incorporated into the γ-secretase complex through binding to transmembrane domain 4 of presenilin 1, J. Biol. Chem. 280, 41967-75.
78. Kim, S. H., and Sisodia, S. S. (2005) Evidence that the "NF" motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2, J. Biol. Chem. 280, 41953-66.
79. Capell, A., Kaether, C., Edbauer, D., Shirotani, K., Merkl, S., Steiner, H., and Haass, C. (2003) Nicastrin interacts with γ-secretase complex components via the N-terminal part of its transmembrane domain, J. Biol. Chem. 278, 52519-23.
80. Fortna, R. R., Crystal, A. S., Morais, V. A., Pijak, D. S., Lee, V. M., and Doms, R. W. (2004) Membrane topology and nicastrin-enhanced endoproteolysis of APH-1, a component of the γ-secretase complex. J. Biol. Chem., 279, 3685-93.
81. Crystal, A. S., Morais, V. A., Pierson, T. C., Pijak, D. S., Carlin, D., Lee, V. M., and Doms, R. W. (2003) Membrane topology of γ-secretase component PEN-2, J. Biol. Chem. 278, 20117-23.
82. Mackinnon, R. (2005) Structural biology. Membrane protein insertion and stability, Science 307, 1425-6.
83. Annaert, W. G., Esselens, C., Baert, V., Boeve, C, Snellings, G., Cupers, P., Craessaerts, K., and De Strooper, B. (2001) Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins, Neuron 32, 579-89.
84. Brunkan, A. L., Martinez, M., Wang, J., Walker, E. S., Beher, D., Shearman, M. S., and Goate, A. M. (2005) Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and γ-secretase activity, J. Neurochem. 94, 1315-28.
85. Kornilova, A. Y., Kim, J., Laudon, H., and Wolfe, M. S. (2006) Deducing the transmembrane domain organization of presenilin-1 in γ-secretase by cysteine disulfide cross-linking, Biochemistry 45, 7598-7604.
86. Saura, C. A., Tomita, T., Soriano, S., Takahashi, M., Leem, J. Y., Honda, T., Koo, E. H., Iwatsubo, T., and Thinakaran, G. (2000) The nonconserved hydrophilic loop domain of presenilin (PS) is not required for PS endoproteolysis or enhanced Aβ42 production mediated by familial early onset Alzheimer's disease-linked PS variants, J. Biol. Chem. 275, 17136-42.
87. Podlisny, M. B., Citron, M., Amarante, P., Sherrington, R., Xia, W., Zhang, J., Diehl, T., Levesque, G., Fraser, P., Haass, C., Koo, E. H., Seubert, P., St George-Hyslop, P., Teplow, D. B., and Selkoe, D. J. (1997) 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. 3, 325-37.
88. Laudon, H., Karlstrom, H., Mathews, P. M., Farmery, M. R., Candy, S. E., Lundkvist, J., Lendahl, U., and Naslund, J. (2004) Functional domains in presenilin 1: The Tyr-288 residue controls γ-secretase activity and endoproteolysis, J. Biol. Chem. 279, 23925-32.
89. Tomita, T., Takikawa, R., Koyama, A., Morohashi, Y., Takasugi, N., Saido, T. C., Maruyama, K., and Iwatsubo, T. (1999) C terminus of presenilin is required for overproduction of amyloidogenic Aβ42 through stabilization and endoproteolysis of presenilin, J. Neurosci. 19, 10627-34.
90. Kaether, C, Capell, A., Edbauer, D., Winkler, E., Novak, B., Steiner, H., and Haass, C. (2004) The presenilin C-terminus is required for ER-retention, nicastrin-binding and γ-secretase activity, EMBO J. 23, 4738-48.
91. Das, C., Berezovska, O., Diehl, T. S., Genet, C., Buldyrev, I., Tsai, J. Y., Hyman, B. T., and Wolfe, M. S. (2003) Designed helical peptides inhibit an intramembrane protease, J. Am. Chem. Soc. 125, 11794-5.
92. Kornilova, A. Y., Bihel, F., Das, C., and Wolfe, M. S. (2005) The initial substrate-binding site of γ-secretase is located on presenilin near the active site, Proc. Natl. Acad. Sci. U.S.A. 102, 3230-5.
93. Bihel, F., Das, C., Bowman, M. J., and Wolfe, M. S. (2004) Discovery of a subnanomolar helical D-tridecapeptide inhibitor of γ-secretase, J. Med. Chem. 47, 3931-3.
94. Searfoss, G. H., Jordan, W. H., Calligaro, D. O., Galbreath, E. J., Schirtzinger, L. M., Berridge, B. R., Gao, H., Higgins, M. A., May, P. C., and Ryan, T. P. (2003) Adipsin: A biomarker of gastrointestinal toxicity mediated by a functional γ-secretase inhibitor, J. Biol. Chem. 278, 46107-16.
95. Wong, G. T., Manfra, D., Poulet, F. M., Zhang, Q., Josien, H., Bara, T., Engstrom, L., Pinzon-Ortiz, M., Fine, J. S., Lee, H. J., Zhang, L., Higgins, G. A., and Parker, E. M. (2004) Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation, J. Biol. Chem. 279, 12876-82.
96. Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., Findlay, K. A., Smith, T. E., Murphy, M. P., Bulter, T., Rang, D. E., Marquez-Sterling, N., Golde, T. E., and Koo, E. H. (2001) A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity, Nature 414, 212-6.
97. Weggen, S., Eriksen, J. L., Sagi, S. A., Pietrzik, C. U., Ozols, V., Fauq, A., Golde, T. E., and Koo, E. H. (2003) Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid β42 production by direct modulation of γ-secretase activity, J. Biol. Chem. 278, 31831-7.
98. Beher, D., Clarke, E. E., Wrigley, J. D., Martin, A. C., Nadin, A., Churcher, I., and Shearman, M. S. (2004) Selected non-steroidal anti-inflammatory drugs and their derivatives target γ-secretase at a novel site. Evidence for an allosteric mechanism, J. Biol. Chem. 279, 43419-26.
99. Okochi, M., Fukumori, A., Jiang, J., Itoh, N., Kimura, R., Steiner, H., Haass, C., Tagami, S., and Takeda, M. (2006) Secretion of the Notch-1 Aβ-like peptide during Notch signaling, J. Biol. Chem. 281, 7890-8.
100. Sato, T., Nyborg, A. C., Iwata, N., Diehl, T. S., Saido, T. C., Golde, T. E., and Wolfe, M. S. (2006) Signal peptide peptidase: Biochemical properties and modulation by nonsteroidal anti-inflammatory drugs, Biochemistry 45 (in press).
101. Netzer, W. J., Dou, F., Cai, D., Veach, D., Jean, S., Li, Y., Bornmann, W. G., Clarkson, B., Xu, H., and Greengard, P. (2003) Gleevec inhibits β-amyloid production but not Notch cleavage, Proc. Natl. Acad. Sci. U.S.A. 100, 12444-9.
102. Fraering, P. C., Ye, W., Lavoie, M. J., Ostaszewski, B. L., Selkoe, D. J., and Wolfe, M. S. (2005) γ-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide binding site, J. Biol. Chem. 280, 41987-96.
103. Wolfe, M. S., and Kopan, R. (2004) Intramembrane proteolysis: Theme and variations, Science 305, 1119-23.
104. Goutte, C., Tsunozaki, M., Hale, V. A., and Priess, J. R. (2002) 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, 775-79.