Structural biology of presenilins and signal peptide peptidases

Journal of Biological Chemistry

Volumn 288, Issue 21, 2013, Pages 14673-14680

  Tomita, Taisuke ^a,c   Iwatsubo, Takeshi ^a,b,c  

^a UNIVERSITY OF TOKYO   (Japan)

^b UNIVERSITY OF TOKYO   (Japan)

^c JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ALZHEIMER DISEASE; CATALYTIC SUBUNITS; HUMAN DISEASE; PRESENILINS; RECENT PROGRESS; SIGNAL PEPTIDE; STRUCTURAL BIOLOGY; X-RAY STRUCTURE;

BIOCHEMISTRY; BIOLOGY;

PROTEINS;

AMYLOID BETA PROTEIN; COFACTOR PROTEIN; GAMMA SECRETASE; MEMBRANE PROTEIN; PEPTIDASE; PRESENILIN; SIGNAL PEPTIDE; SIGNAL PEPTIDE PEPTIDASE; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; BIOPHYSICS; CATALYSIS; CELLULAR DISTRIBUTION; COMPLEX FORMATION; DRUG TARGETING; ENZYME ACTIVE SITE; ENZYME CHEMISTRY; ENZYME REGULATION; ENZYME STRUCTURE; HUMAN; IMMUNOREGULATION; MOLECULAR BIOLOGY; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN CLEAVAGE; PROTEIN FAMILY; PROTEIN FUNCTION; PROTEIN MOTIF; PROTEIN STRUCTURE; SHORT SURVEY;

INTRAMEMBRANE PROTEOLYSIS; MEMBRANE PROTEINS; PRESENILIN; PROTEOLYTIC ENZYMES; SECRETASES;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; ARCHAEA; ARCHAEAL PROTEINS; CATALYTIC DOMAIN; HUMANS; MEMBRANE PROTEINS; PRESENILINS; PROTEIN STRUCTURE, TERTIARY; SERINE ENDOPEPTIDASES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84878256048     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.R113.463281     Document Type: Short Survey

References (100)

1. De Strooper, B., Iwatsubo, T., and Wolfe, M. S. (2012) Presenilins and γ-secretase: structure, function, and role in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006304
2. 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 Aβ monoclonals: evidence that an initially deposited species is Aβ42(43). Neuron 13, 45-53
3. Jarrett, J. T., Berger, E. P., and Lansbury, P. T., Jr. (1993) The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693-4697 (Pubitemid 23162022)
4. Sato, C., Zhao, G., and Ilagan, M. X. (2012) An overview of notch signaling in adult tissue renewal and maintenance. Curr. Alzheimer Res. 9, 227-240
5. Tomita, T. (2009) Secretase inhibitors and modulators for Alzheimer's disease treatment. Expert. Rev. Neurother. 9, 661-679
6. Imbimbo, B. P., and Giardina, G. A. (2011) γ-Secretase inhibitors and modulators for the treatment of Alzheimer's disease: disappointments and hopes. Curr. Top. Med. Chem. 11, 1555-1570
7. Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J. F., Bruni, A. C., Montesi, M. P., Sorbi, S., Rainero, I., Pinessi, L., Nee, L., Chumakov, I., Pollen, D., Brookes, A., Sanseau, P., Polinsky, R. J., Wasco, W., Da Silva, H. A., Haines, J. L., Perkicak-Vance, M. A., Tanzi, R. E., Roses, A. D., Fraser, P. E., Rommens, J. M., and St George-Hyslop, P. H. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754-760
8. Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., and Tsuda, T. (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, 775-778
9. Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C. E., Jondro, P. D., Schmidt, S. D., and Wang, K. (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973-977
10. Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C. M., Perez-tur, J., Hutton, 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, 710-713 (Pubitemid 26360645)
11. Borchelt, D. R., Ratovitski, T., van Lare, J., Lee, M. K., Gonzales, V., Jenkins, N. A., Copeland, N. G., Price, D. L., and Sisodia, S. S. (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19, 939-945 (Pubitemid 27471397)
12. 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 (Pubitemid 27019143)
13. Tomita, T., Maruyama, K., Saido, T. C., Kume, H., Shinozaki, K., Tokuhiro, S., Capell, A., Walter, J., Grünberg, J., Haass, C., Iwatsubo, T., and Obata, K. (1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid β protein ending at the 42nd (or 43rd) residue. Proc. Natl. Acad. Sci. U.S.A. 94, 2025-2030 (Pubitemid 27113955)
14. 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, 387-390 (Pubitemid 28093512)
15. Naruse, S., Thinakaran, G., Luo, J. J., Kusiak, J. W., Tomita, T., Iwatsubo, T., Qian, X., Ginty, D. D., Price, D. L., Borchelt, D. R., Wong, P. C., and Sisodia, S. S. (1998) Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron 21, 1213-1221 (Pubitemid 29018089)
16. 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 pre-senilin-1. Nat. Cell Biol. 2, 428-434
17. 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, 689-694 (Pubitemid 30428655)
18. 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, 513-517
19. Steiner, H., Kostka, M., Romig, H., Basset, G., Pesold, B., Hardy, J., Capell, A., Meyn, L., Grim, M. L., Baumeister, R., Fechteler, K., and Haass, C. (2000) Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nat. Cell Biol. 2, 848-851
20. LaPointe, C. F., and Taylor, R. K. (2000) The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases. J. Biol. Chem. 275, 1502-1510 (Pubitemid 30051212)
21. 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, 2215-2218 (Pubitemid 34680305)
22. Edbauer, D., Winkler, E., Regula, J. T., Pesold, B., Steiner, H., and Haass, C. (2003) Reconstitution of γ-secretase activity. Nat. Cell Biol. 5, 486-488
23. Hayashi, I., Urano, Y., Fukuda, R., Isoo, N., Kodama, T., Hamakubo, T., Tomita, T., and Iwatsubo, T. (2004) Selective reconstitution and recovery of functional γ-secretase complex on budded baculovirus particles. J. Biol. Chem. 279, 38040-38046 (Pubitemid 39195520)
24. Hu, J., Xue, Y., Lee, S., and Ha, Y. (2011) The crystal structure of GXGD membrane protease FlaK. Nature 475, 528-531
25. Li, X., Dang, S., Yan, C., Gong, X., Wang, J., and Shi, Y. (2013) Structure of a presenilin family intramembrane aspartate protease. Nature 493, 56-61
26. 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
27. 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, 775-779 (Pubitemid 34106586)
28. 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 (Pubitemid 34778398)
29. 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, 181-190 (Pubitemid 26251602)
30. 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, 438-441 (Pubitemid 36411397)
31. Tarassishin, L., Yin, Y. I., Bassit, B., and Li, Y. M. (2004) Processing of Notch and amyloid precursor protein by γ-secretase is spatially distinct. Proc. Natl. Acad. Sci. U.S.A. 101, 17050-17055 (Pubitemid 39627772)
32. Kaether, C., Lammich, S., Edbauer, D., Ertl, M., Rietdorf, J., Capell, A., Steiner, H., and Haass, C. (2002) Presenilin-1 affects trafficking and processing of βAPP and is targeted in a complex with nicastrin to the plasma membrane. J. Cell Biol. 158, 551-561 (Pubitemid 34851713)
33. Hayashi, I., Takatori, S., Urano, Y., Miyake, Y., Takagi, J., Sakata-Yanagimoto, M., Iwanari, H., Osawa, S., Morohashi, Y., Li, T., Wong, P. C., Chiba, S., Kodama, T., Hamakubo, T., Tomita, T., and Iwatsubo, T. (2012) Neutralization of the γ-secretase activity by monoclonal antibody against extracellular domain of nicastrin. Oncogene 31, 787-798
34. Ahn, K., Shelton, C. C., Tian, Y., Zhang, X., Gilchrist, M. L., Sisodia, S. S., and Li, Y. M. (2010) Activation and intrinsic γ-secretase activity of presenilin 1. Proc. Natl. Acad. Sci. U.S.A. 107, 21435-21440
35. Sato, C., Morohashi, Y., Tomita, T., and Iwatsubo, T. (2006) Structure of the catalytic pore of γ-secretase probed by the accessibility of substituted cysteines. J. Neurosci. 26, 12081-12088 (Pubitemid 44772118)
36. Sato, C., Takagi, S., Tomita, T., and Iwatsubo, T. (2008) The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the γ-secretase. J. Neurosci. 28, 6264-6271
37. Takagi, S., Tominaga, A., Sato, C., Tomita, T., and Iwatsubo, T. (2010) Participation of transmembrane domain 1 of presenilin 1 in the catalytic pore structure of the γ-secretase. J. Neurosci. 30, 15943-15950
38. Karlin, A., and Akabas, M. H. (1998) Substituted-cysteine accessibility method. Methods Enzymol. 293, 123-145 (Pubitemid 29342485)
39. Loo, T. W., and Clarke, D. M. (1999) Determining the structure and mechanism of the human multidrug resistance P-glycoprotein using cysteine-scanning mutagenesis and thiol-modification techniques. Biochim. Biophys. Acta 1461, 315-325
40. Tolia, A., Chávez-Gutiérrez, L., and De Strooper, B. (2006) Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the γ-secretase complex. J. Biol. Chem. 281, 27633-27642 (Pubitemid 44401788)
41. Tolia, A., Horré, K., and De Strooper, B. (2008) Transmembrane domain 9 of presenilin determines the dynamic conformation of the catalytic site of γ-secretase. J. Biol. Chem. 283, 19793-19803
42. Takeo, K., Watanabe, N., Tomita, T., and Iwatsubo, T. (2012) Contribution of the γ-secretase subunits to the formation of catalytic pore of presenilin 1 protein. J. Biol. Chem. 287, 25834-25843
43. 2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell 126, 981-993
44. Takami, M., and Funamoto, S. (2012) γ-Secretase-dependent proteolysis of transmembrane domain of amyloid precursor protein: successive triand tetrapeptide release in amyloid β-protein production. Int. J. Alzheimers Dis. 2012, 591392
45. Gu, Y., Misonou, H., Sato, T., Dohmae, N., Takio, K., and Ihara, Y. (2001) Distinct intramembrane cleavage of the β-amyloid precursor protein family resembling γ-secretase-like cleavage of Notch. J. Biol. Chem. 276, 35235-35238
46. Yu, C., Kim, S. H., Ikeuchi, T., Xu, H., Gasparini, L., Wang, R., and Sisodia, S. S. (2001) Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminalZ fragment γ. Evidence for distinct mechanisms involved in γ-secretase processing of the APP and Notch1 transmembrane domains. J. Biol. Chem. 276, 43756-43760
47. Sato, T., Tang, T. C., Reubins, G., Fei, J. Z., Fujimoto, T., Kienlen-Campard, P., Constantinescu, S. N., Octave, J. N., Aimoto, S., and Smith, S. O. (2009) A helix-to-coil transition at the ε-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis. Proc. Natl. Acad. Sci. U.S.A. 106, 1421-1426
48. Pester, O., Barrett, P. J., Hornburg, D., Hornburg, P., Pröbstle, R., Widmaier, S., Kutzner, C., Dürrbaum, M., Kapurniotu, A., Sanders, C. R., Scharnagl, C., and Langosch, D. (2013) The backbone dynamics of the amyloid precursor protein transmembrane helix provides a rationale for the sequential cleavage mechanism of γ-secretase. J. Am. Chem. Soc. 135, 1317-1329
49. Qi-Takahara, Y., Morishima-Kawashima, M., Tanimura, Y., Dolios, G., Hirotani, N., Horikoshi, Y., Kametani, F., Maeda, M., Saido, T. C., Wang, R., and Ihara, Y. (2005) Longer forms of amyloid β protein: implications for the mechanism of intramembrane cleavage by γ-secretase. J. Neurosci. 25, 436-445 (Pubitemid 40105614)
50. Takami, M., Nagashima, Y., Sano, Y., Ishihara, S., Morishima-Kawashima, M., Funamoto, S., and Ihara, Y. (2009) γ-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of β-carboxyl terminal fragment. J. Neurosci. 29, 13042-13052
51. 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 γ 49-99 of β-amyloid precursor protein. J. Biol. Chem. 278, 24294-24301
52. Wang, J., Beher, D., Nyborg, A. C., Shearman, M. S., Golde, T. E., and Goate, A. (2006) C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation. J. Neurochem. 96, 218-227
53. Tomita, T., Watabiki, T., Takikawa, R., Morohashi, Y., Takasugi, N., Kopan, R., De Strooper, B., and Iwatsubo, T. (2001) The first proline of PALP motif at theCterminus of presenilins is obligatory for stabilization, complex formation, and γ-secretase activities of presenilins. J. Biol. Chem. 276, 33273-33281
54. Morohashi, Y., Kan, T., Tominari, Y., Fuwa, H., Okamura, Y., Watanabe, N., Sato, C., Natsugari, H., Fukuyama, T., Iwatsubo, T., and Tomita, T. (2006) C-terminal fragment of presenilin is the molecular target of a dipeptidic γ-secretase-specific inhibitor DAPT (N-[N-(3,5-difluoro-phenacetyl)-L- alanyl]-S-phenylglycine t-butyl ester). J. Biol. Chem. 281, 14670-14676 (Pubitemid 43855171)
55. 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, 11794-11795 (Pubitemid 37175395)
56. 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, 3230-3235 (Pubitemid 40328028)
57. Imamura, Y., Watanabe, N., Umezawa, N., Iwatsubo, T., Kato, N., Tomita, T., and Higuchi, T. (2009) Inhibition of γ-secretase activity by helical β-peptide foldamers. J. Am. Chem. Soc. 131, 7353-7359
58. Imamura, Y., Umezawa, N., Osawa, S., Shimada, N., Higo, T., Yokoshima, S., Fukuyama, T., Iwatsubo, T., Kato, N., Tomita, T., and Higuchi, T. (2013) Effect of helical conformation and side chain structure on γ-secretase inhibition by β-peptide foldamers: insight into substrate recognition. J. Med. Chem. 56, 1443-1454
59. Watanabe, N.,Takagi, S., Tominaga, A., Tomita, T., and Iwatsubo, T. (2010) Functional analysis of the transmembrane domains of presenilin 1. Participation of transmembrane domains 2 and 6 in the formation of initial substrate-binding site of γ-secretase. J. Biol. Chem. 285, 19738-19746
60. Takagi-Niidome, S., Osawa, S., Tomita, T., and Iwatsubo, T. (2013) Inhibition of γ-secretase activity by a monoclonal antibody against the extracellular hydrophilic loop of presenilin 1. Biochemistry 52, 61-69
61. Ohki, Y., Higo, T., Uemura, K., Shimada, N., Osawa, S., Berezovska, O., Yokoshima, S., Fukuyama, T., Tomita, T., and Iwatsubo, T. (2011) Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1. EMBO J. 30, 4815-4824
62. Okochi, M., Tagami, S., Yanagida, K., Takami, M., Kodama, T. S., Mori, K., Nakayama, T., Ihara, Y., and Takeda, M. (2013) γ-Secretase modulators and presenilin 1 mutants act differently on presenilin/γ-secretase function to cleave Aβ42 and Aβ43. Cell Rep. 3, 42-51
63. Shah, S., Lee, S. F., Tabuchi, K., Hao, Y. H., Yu, C., LaPlant, Q., Ball, H., Dann, C. E., 3rd, Südhof, T., and Yu, G. (2005) Nicastrin functions as a γ-secretase-substrate receptor. Cell 122, 435-447
64. Narayanan, S., Sato, T., and Wolfe, M. S. (2007) A C-terminal region of signal peptide peptidase defines a functional domain for intramembrane aspartic protease catalysis. J. Biol. Chem. 282, 20172-20179 (Pubitemid 47100000)
65. Filipović, A., Gronau, J. H., Green, A. R., Wang, J., Vallath, S., Shao, D., Rasul, S., Ellis, I. O., Yagüe, E., Sturge, J., and Coombes, R. C. (2011) Biological and clinical implications of nicastrin expression in invasive breast cancer. Breast Cancer Res. Treat. 125, 43-53
66. Zhang, X., Hoey, R. J., Lin, G., Koide, A., Leung, B., Ahn, K., Dolios, G., Paduch, M., Ikeuchi, T., Wang, R., Li, Y. M., Koide, S., and Sisodia, S. S. (2012) Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of γ-secretase using synthetic antibodies. Proc. Natl. Acad. Sci. U.S.A. 109, 8534-8539
67. Thathiah, A., Horré, K., Snellinx, A., Vandewyer, E., Huang, Y., Ciesielska, M., De Kloe, G., Munck, S., and De Strooper, B. (2013) β-Arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease. Nat. Med. 19, 43-49
68. Liu, X., Zhao, X., Zeng, X., Bossers, K., Swaab, D. F., Zhao, J., and Pei, G. (2013) β-Arrestin 1 regulates γ-secretase complex assembly and modulates amyloid-β pathology. Cell Res. 23, 351-365
69. Shirotani, K., Edbauer, D., Prokop, S., Haass, C., and Steiner, H. (2004) Identification of distinct γ-secretase complexes with different APH-1 variants. J. Biol. Chem. 279, 41340-41345 (Pubitemid 39313572)
70. 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, 37213-37222 (Pubitemid 37175237)
71. Niimura, M., Isoo, N., Takasugi, N., Tsuruoka, M., Ui-Tei, K., Saigo, K., Morohashi, Y., Tomita, T., and Iwatsubo, T. (2005) Aph-1 contributes to the stabilization and trafficking of the γ-secretase complex through mechanisms involving intermolecular and intramolecular interactions. J. Biol. Chem. 280, 12967-12975
72. 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, 4738-4748 (Pubitemid 40069704)
73. Bergman, A., Laudon, H., Winblad, B., Lundkvist, J., and Näslund, J. (2004) The extreme C terminus of presenilin 1 is essential for γ-secretase complex assembly and activity. J. Biol. Chem. 279, 45564-45572 (Pubitemid 39491543)
74. 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, 41967-41975 (Pubitemid 43023165)
75. 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, 41953-41966
76. Prokop, S., Shirotani, K., Edbauer, D., Haass, C., and Steiner, H. (2004) Requirement of PEN-2 for stabilization of the presenilin N/C-terminal fragment heterodimer within the γ-secretase complex. J. Biol. Chem. 279, 23255-23261 (Pubitemid 38685633)
77. Isoo, N., Sato, C., Miyashita, H., Shinohara, M., Takasugi, N., Morohashi, Y., Tsuji, S., Tomita, T., and Iwatsubo, T. (2007) Aβ42 overproduction associated with structural changes in the catalytic pore of γ-secretase. Common effects of Pen-2 N-terminal elongation and fenofibrate. J. Biol. Chem. 282, 12388-12396 (Pubitemid 47100594)
78. Kounnas, M. Z., Danks, A. M., Cheng, S., Tyree, C., Ackerman, E., Zhang, X., Ahn, K., Nguyen, P., Comer, D., Mao, L., Yu, C., Pleynet, D., Digregorio, P. J., Velicelebi, G., Stauderman, K. A., Comer, W. T., Mobley, W. C., Li, Y. M., Sisodia, S. S., Tanzi, R. E., and Wagner, S. L. (2010) Modulation of γ-secretase reduces β-amyloid deposition in a transgenic mouse model of Alzheimer's disease. Neuron 67, 769-780
79. Ogura, T., Mio, K., Hayashi, I., Miyashita, H., Fukuda, R., Kopan, R., Kodama, T., Hamakubo, T., Iwatsubo, T., Tomita, T., and Sato, C. (2006) Three-dimensional structure of the γ-secretase complex. Biochem. Biophys. Res. Commun. 343, 525-534
80. Osenkowski, P., Li, H., Ye, W., Li, D., Aeschbach, L., Fraering, P. C., Wolfe, M. S., and Selkoe, D. J. (2009) Cryoelectron microscopy structure of purified γ-secretase at 12 Å resolution. J. Mol. Biol. 385, 642-652
81. Renzi, F., Zhang, X., Rice, W. J., Torres-Arancivia, C., Gomez-Llorente, Y., Diaz, R., Ahn, K., Yu, C., Li, Y. M., Sisodia, S. S., and Ubarretxena-Belandia, I. (2011) Structure of γ-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy. J. Biol. Chem. 286, 21440-21449
82. Golde, T. E., Wolfe, M. S., and Greenbaum, D. C. (2009) Signal peptide peptidases: a family of intramembrane-cleaving proteases that cleave type 2 transmembrane proteins. Semin. Cell Dev. Biol. 20, 225-230
83. Lemberg, M. K., Bland, F. A., Weihofen, A., Braud, V. M., and Martoglio, B. (2001) Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes. J. Immunol. 167, 6441-6446 (Pubitemid 33081577)
84. McLauchlan, J., Lemberg, M. K., Hope, G., and Martoglio, B. (2002) Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. EMBO J. 21, 3980-3988 (Pubitemid 34857431)
85. Okamoto, K., Moriishi, K., Miyamura, T., and Matsuura, Y. (2004) Intramembrane proteolysis and endoplasmic reticulum retention of hepatitis C virus core protein. J. Virol. 78, 6370-6380 (Pubitemid 38715935)
86. Targett-Adams, P., Schaller, T., Hope, G., Lanford, R. E., Lemon, S. M., Martin, A., and McLauchlan, J. (2006) Signal peptide peptidase cleavage of GB virus B core protein is required for productive infection in vivo. J. Biol. Chem. 281, 29221-29227 (Pubitemid 44507065)
87. Friedmann, E., Hauben, E., Maylandt, K., Schleeger, S., Vreugde, S., Lichtenthaler, S. F., Kuhn, P. H., Stauffer, D., Rovelli, G., and Martoglio, B. (2006) SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 production. Nat. Cell Biol. 8, 843-848 (Pubitemid 44151587)
88. Fluhrer, R., Grammer, G., Israel, L., Condron, M. M., Haffner, C., Friedmann, E., Böhland, C., Imhof, A., Martoglio, B., Teplow, D. B., and Haass, C. (2006) A γ-secretase-like intramembrane cleavage of TNFα by the GxGD aspartyl protease SPPL2b. Nat. Cell Biol. 8, 894-896 (Pubitemid 44151595)
89. Beisner, D. R., Langerak, P., Parker, A. E., Dahlberg, C., Otero, F. J., Sutton, S. E., Poirot, L., Barnes, W., Young, M. A., Niessen, S., Wiltshire, T., Bodendorf, U., Martoglio, B., Cravatt, B., and Cooke, M. P. (2013) The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain. J. Exp. Med. 210, 23-30
90. - dendritic cells require the intramembrane endopeptidase SPPL2A. J. Exp. Med. 210, 31-40
91. Schneppenheim, J., Dressel, R., Hüttl, S., Lüllmann-Rauch, R., Engelke, M., Dittmann, K., Wienands, J., Eskelinen, E. L., Hermans-Borgmeyer, I., Fluhrer, R., Saftig, P., and Schröder, B. (2013) The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain. J. Exp. Med. 210, 41-58
92. Kornilova, A. Y., Das, C., and Wolfe, M. S. (2003) Differential effects of inhibitors on the γ-secretase complex. Mechanistic implications. J. Biol. Chem. 278, 16470-16473 (Pubitemid 36799504)
93. Weihofen, A., Lemberg, M. K., Friedmann, E., Rueeger, H., Schmitz, A., Paganetti, P., Rovelli, G., and Martoglio, B. (2003) Targeting presenilintype aspartic protease signal peptide peptidase with γ-secretase inhibitors. J. Biol. Chem. 278, 16528-16533 (Pubitemid 36799513)
94. 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 antiinflammatory drugs. Biochemistry 45, 8649-8656 (Pubitemid 44078885)
95. Fuwa, H., Takahashi, Y., Konno, Y., Watanabe, N., Miyashita, H., Sasaki, M., Natsugari, H., Kan, T., Fukuyama, T., Tomita, T., and Iwatsubo, T. (2007) Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic γ-secretase inhibitors. ACS Chem. Biol. 2, 408-418 (Pubitemid 350001562)
96. Miyashita, H., Maruyama, Y., Isshiki, H., Osawa, S., Ogura, T., Mio, K., Sato, C., Tomita, T., and Iwatsubo, T. (2011) Three-dimensional structure of the signal peptide peptidase. J. Biol. Chem. 286, 26188-26197
97. Sobhanifar, S., Schneider, B., Löhr, F., Gottstein, D., Ikeya, T., Mlynarczyk, K., Pulawski, W., Ghoshdastider, U., Kolinski, M., Filipek, S., Güntert, P., Bernhard, F., and Dötsch, V. (2010) Structural investigation of the C-terminal catalytic fragment of presenilin 1. Proc. Natl. Acad. Sci. U.S.A. 107, 9644-9649
98. Tomita, T., Tokuhiro, S., Hashimoto, T., Aiba, K., Saido, T. C., Maruyama, K., and Iwatsubo, T. (1998) Molecular dissection of domains in mutant presenilin 2 that mediate overproduction of amyloidogenic forms of amyloid β peptides. Inability of truncated forms of PS2 with familial Alzheimer's disease mutation to increase secretion of Aβ42. J. Biol. Chem. 273, 21153-21160 (Pubitemid 28385404)
99. Torres-Arancivia, C., Ross, C. M., Chavez, J., Assur, Z., Dolios, G., Mancia, F., and Ubarretxena-Belandia, I. (2010) Identification of an archaeal presenilin-like intramembrane protease. PLoS ONE 5, e13072
100. Chávez-Gutiérrez, L., Bammens, L., Benilova, I., Vandersteen, A., Benurwar, M., Borgers, M., Lismont, S., Zhou, L., Van Cleynenbreugel, S., Esselmann, H., Wiltfang, J., Serneels, L., Karran, E., Gijsen, H., Schymkowitz, J., Rousseau, F., Broersen, K., and De Strooper, B. (2012) The mechanism of γ-secretase dysfunction in familial Alzheimer disease. EMBO J. 31, 2261-2274