The dynamic conformational landscape of γ-secretase

Journal of Cell Science

Volumn 128, Issue 3, 2015, Pages 589-598

  Elad, Nadav ^a,b   de Strooper, Bart ^a,b,c   Lismont, Sam ^a,b   Hagen, Wim ^d   Veugelen, Sarah ^a,b   Arimon, Muriel ^e   Horré, Katrien ^a,b   Berezovska, Oksana ^d   Sachse, Carsten ^d   Chávez Gutiérrez, Luciá ^a,b  

^a DEPARTMENT OF PLANT SYSTEMS BIOLOGY   (Belgium)

^b UNIVERSITY HOSPITALS LEUVEN   (Belgium)

^c UNIVERSITY COLLEGE LONDON   (United Kingdom)

^d EUROPEAN MOLECULAR BIOLOGY LABORATORY   (Germany)

^e MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Alzheimer disease; Conformational landscape; Regulated intramembrane proteolysis; Single particle electron microscopy; secretase

Indexed keywords

AMYLOID BETA PROTEIN; GAMMA SECRETASE; NANOBODY; NICASTRIN; FLAVINE ADENINE NUCLEOTIDE; MEMBRANE PROTEIN; PROTEIN SUBUNIT; SECRETASE;

ALLOSTERISM; ALZHEIMER DISEASE; ARTICLE; BINDING SITE; CONTROLLED STUDY; ELECTRON MICROSCOPY; ENZYME CONFORMATION; ENZYME PURIFICATION; MUTATION; PRIORITY JOURNAL; PROTEINASE INHIBITION; STEADY STATE; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL LINE; DRUG EFFECTS; ENZYME ACTIVE SITE; GENETICS; HEK293 CELL LINE; HUMAN; INSECT; METABOLISM; PROTEIN CONFORMATION; PROTEIN SUBUNIT;

ALZHEIMER DISEASE; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; CATALYTIC DOMAIN; CELL LINE; FLAVIN-ADENINE DINUCLEOTIDE; HEK293 CELLS; HUMANS; INSECTS; MEMBRANE GLYCOPROTEINS; MICROSCOPY, ELECTRON; PROTEIN CONFORMATION; PROTEIN SUBUNITS;

EID: 84961331937     PISSN: 00219533     EISSN: 14779137     Source Type: Journal    
DOI: 10.1242/jcs.164384     Document Type: Article

References (57)

1. Acx, H., Chávez-Gutiérrez, L., Serneels, L., Lismont, S., Benurwar, M., Elad, N. and De Strooper, B. (2014). Signature amyloid β profiles are produced by different γ-secretase complexes. J. Biol. Chem. 289, 4346-4355.
2. 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, 579-589.
3. Barthet, G., Shioi, J., Shao, Z., Ren, Y., Georgakopoulos, A. and Robakis, N. K. (2011). Inhibitors of γ-secretase stabilize the complex and differentially affect processing of amyloid precursor protein and other substrates. FASEB J. 25, 2937-2946.
4. Benkovic, S. J., Hammes, G. G. and Hammes-Schiffer, S. (2008). Free-energy landscape of enzyme catalysis. Biochemistry 47, 3317-3321.
5. Berezovska, O., Lleo, A., Herl, L. D., Frosch, M. P., Stern, E. A., Bacskai, B. J. and Hyman, B. T. (2005). Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein. J. Neurosci. 25, 3009-3017.
6. Boehr, D. D., Nussinov, R. and Wright, P. E. (2009). The role of dynamic conformational ensembles in biomolecular recognition. Nat. Chem. Biol. 5, 789-796.
7. Capell, A., Grünberg, 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, 3205-3211.
8. Chae, P. S., Rasmussen, S. G., Rana, R. R., Gotfryd, K., Chandra, R., Goren, M. A., Kruse, A. C., Nurva, S., Loland, C. J., Pierre, Y. et al. (2010). Maltoseneopentylglycol (MNG) amphiphiles for solubilization, stabilization and crystallization of membrane proteins. Nat. Methods 7, 1003-1008.
9. Chávez-Gutírrez, L., Tolia, A., Maes, E., Li, T., Wong, P. C. and de Strooper, B. (2008). Glu(332) in the Nicastrin ectodomain is essential for gammasecretase complex maturation but not for its activity. J. Biol. Chem. 283, 20096-20105.
10. Chávez-Gutírrez, L., Bammens, L., Benilova, I., Vandersteen, A., Benurwar, M., Borgers, M., Lismont, S., Zhou, L., Van Cleynenbreugel, S., Esselmann, H. et al. (2012). The mechanism of c-Secretase dysfunction in familial Alzheimer disease. EMBO J. 31, 2261-2274.
11. Cianfrocco, M. A., Kassavetis, G. A., Grob, P., Fang, J., Juven-Gershon, T., Kadonaga, J. T. and Nogales, E. (2013). Human TFIID binds to core promoter DNA in a reorganized structural state. Cell 152, 120-131.
12. 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.
13. De Strooper, B. (2003). Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 38, 9-12.
14. De Strooper, B. and Annaert, W. (2010). Novel research horizons for presenilins and γ-secretases in cell biology and disease. Annu. Rev. Cell Dev. Biol. 26, 235-260.
15. Elad, N., Farr, G. W., Clare, D. K., Orlova, E. V., Horwich, A. L. and Saibil, H. R. (2007). Topologies of a substrate protein bound to the chaperonin GroEL. Mol. Cell 26, 415-426.
16. Elad, N., Clare, D. K., Saibil, H. R. and Orlova, E. V. (2008). Detection and separation of heterogeneity in molecular complexes by statistical analysis of their two-dimensional projections. J. Struct. Biol. 162, 108-120.
17. 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). Transitionstate analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nat. Cell Biol. 2, 428-434.
18. Esselens, C., Oorschot, V., Baert, V., Raemaekers, T., Spittaels, K., Serneels, L., Zheng, H., Saftig, P., De Strooper, B., Klumperman, J. et al. (2004). Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J. Cell Biol. 166, 1041-1054.
19. Fischer, N., Konevega, A. L., Wintermeyer, W., Rodnina, M. V. and Stark, H. (2010). Ribosome dynamics and tRNA movement by time-resolved electron cryomicroscopy. Nature 466, 329-333.
20. Frank, J., Radermacher, M., Penczek, P., Zhu, J., Li, Y., Ladjadj, M. and Leith, A. (1996). SPIDER and WEB: processing and visualization of images in 3D electron microscopy and related fields. J. Struct. Biol. 116, 190-199.
21. Guix, F. X., Wahle, T., Vennekens, K., Snellinx, A., Chávez-Gutírrez, L., Ill-Raga, G., Ramos-Fernandez, E., Guardia-Laguarta, C., Lleó, A., Arimon, M. et al. (2012). Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease. EMBO Mol. Med. 4, 660-673.
22. Lazarov, V. K., Fraering, P. C., Ye, W., Wolfe, M. S., Selkoe, D. J. and Li, H. (2006). Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores. Proc. Natl. Acad. Sci. USA 103, 6889-6894.
23. 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. et al. (2000). Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405, 689-694.
24. 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.
25. Li, Y., Lu, S. H., Tsai, C. J., Bohm, C., Qamar, S., Dodd, R. B., Meadows, W., Jeon, A., McLeod, A., Chen, F. et al. (2014). Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes. Structure 22, 125-135.
26. Lleó, A., Berezovska, O., Herl, L., Raju, S., Deng, A., Bacskai, B. J., Frosch, M. P., Irizarry, M. and Hyman, B. T. (2004). Nonsteroidal anti-inflammatory drugs lower Abeta42 and change presenilin 1 conformation. Nat. Med. 10, 1065-1066.
27. Lu, P., Bai, X. C., Ma, D., Xie, T., Yan, C., Sun, L., Yang, G., Zhao, Y., Zhou, R., Scheres, S. H. et al. (2014). Three-dimensional structure of human γ-secretase. Nature 512, 166-170.
28. Mastronarde, D. N. (2005). Automated electron microscope tomography using robust prediction of specimen movements. J. Struct. Biol. 152, 36-51.
29. Mindell, J. A. and Grigorieff, N. (2003). Accurate determination of local defocus and specimen tilt in electron microscopy. J. Struct. Biol. 142, 334-347.
30. Motlagh, H. N., Wrabl, J. O., Li, J. and Hilser, V. J. (2014). The ensemble nature of allostery. Nature 508, 331-339.
31. Nygaard, R., Zou, Y., Dror, R. O., Mildorf, T. J., Arlow, D. H., Manglik, A., Pan, A. C., Liu, C. W., Fung, J. J., Bokoch, M. P. et al. (2013). The dynamic process of β(2)-adrenergic receptor activation. Cell 152, 532-542.
32. Ogura, T., Mio, K., Hayashi, I., Miyashita, H., Fukuda, R., Kopan, R., Kodama, T., Hamakubo, T., Iwatsubo, T., Tomita, T. et al. (2006). Three-dimensional structure of the gamma-secretase complex. Biochem. Biophys. Res. Commun. 343, 525-534.
33. Osenkowski, P., Li, H., Ye, W., Li, D., Aeschbach, L., Fraering, P. C., Wolfe, M. S., Selkoe, D. J. and Li, H. (2009). Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution. J. Mol. Biol. 385, 642-652.
34. Pardon, E., Laeremans, T., Triest, S., Rasmussen, S. G., Wohlkönig, A., Ruf, A., Muyldermans, S., Hol, W. G., Kobilka, B. K. and Steyaert, J. (2014). A general protocol for the generation of Nanobodies for structural biology. Nat. Protoc. 9, 674-693.
35. Perez-Tur, J., Froelich, S., Prihar, G., Crook, R., Baker, M., Duff, K., Wragg, M., Busfield, F., Lendon, C., Clark, R. F. et al. (1995). A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport 7, 297-301.
36. Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C. and Ferrin, T. E. (2004). UCSF Chimera-a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605-1612.
37. Radermacher, M., Wagenknecht, T., Verschoor, A. and Frank, J. (1987). Threedimensional reconstruction from a single-exposure, random conical tilt series applied to the 50S ribosomal subunit of Escherichia coli. J. Microsc. 146, 113-136
38. Rath, B. K. and Frank, J. (2004). Fast automatic particle picking from cryoelectron micrographs using a locally normalized cross-correlation function: a case study. J. Struct. Biol. 145, 84-90.
39. 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. et al. (2011). Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy. J. Biol. Chem. 286, 21440-21449.
40. Rosenthal, P. B. and Henderson, R. (2003). Optimal determination of particle orientation, absolute hand, and contrast loss in single-particle electron cryomicroscopy. J. Mol. Biol. 333, 721-745.
41. Sato, C., Morohashi, Y., Tomita, T. and Iwatsubo, T. (2006). Structure of the catalytic pore of gamma-secretase probed by the accessibility of substituted cysteines. J. Neurosci. 26, 12081-12088.
42. Scheres, S. H. (2012). RELION: implementation of a Bayesian approach to cryo-EM structure determination. J. Struct. Biol. 180, 519-530.
43. Scheres, S. H. and Chen, S. (2012). Prevention of overfitting in cryo-EM structure determination. Nat. Methods 9, 853-854.
44. Selkoe, D. J. and Wolfe, M. S. (2007). Presenilin: running with scissors in the membrane. Cell 131, 215-221.
45. Serneels, L., Van Biervliet, J., Craessaerts, K., Dejaegere, T., Horré, K., Van Houtvin, T., Esselmann, H., Paul, S., Schäfer, M. K., Berezovska, O. et al. (2009). gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease. Science 324, 639-642.
46. 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 gammasecretase- substrate receptor. Cell 122, 435-447.
47. Shelton, C. C., Zhu, L., Chau, D., Yang, L., Wang, R., Djaballah, H., Zheng, H. and Li, Y. M. (2009). Modulation of gamma-secretase specificity using small molecule allosteric inhibitors. Proc. Natl. Acad. Sci. USA 106, 20228-20233.
48. Takagi, J., Petre, B. M., Walz, T. and Springer, T. A. (2002). Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110, 599-11.
49. Tang, G., Peng, L., Baldwin, P. R., Mann, D. S., Jiang, W., Rees, I. and Ludtke, S. J. (2007). EMAN2: an extensible image processing suite for electron microscopy. J. Struct. Biol. 157, 38-46.
50. Thinakaran, G., Borchelt, D. R., Lee, M. K., Slunt, H. H., Spitzer, L., Kim, G., Ratovitsky, T., Davenport, F., Nordstedt, C., Seeger, M. et al. (1996). Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181-190.
51. Tolia, A., Chávez-Gutírrez, L. and De Strooper, B. (2006). Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the gamma-secretase complex. J. Biol. Chem. 281, 27633-27642.
52. Uemura, K., Farner, K. C., Hashimoto, T., Nasser-Ghodsi, N., Wolfe, M. S., Koo, E. H., Hyman, B. T. and Berezovska, O. (2010). Substrate docking to csecretase allows access of γ-secretase modulators to an allosteric site. Nat. Commun. 1, 130.
53. van Heel, M., Harauz, G., Orlova, E. V., Schmidt, R. and Schatz, M. (1996). A new generation of the IMAGIC image processing system. J. Struct. Biol. 116, 17-24.
54. Wahlster, L., Arimon, M., Nasser-Ghodsi, N., Post, K. L., Serrano-Pozo, A., Uemura, K. and Berezovska, O. (2013). Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer's disease. Acta Neuropathol. 125, 187-199.
55. 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 gamma-secretase activity. Nature 398, 513-517.
56. Xie, T., Yan, C., Zhou, R., Zhao, Y., Sun, L., Yang, G., Lu, P., Ma, D. and Shi, Y. (2014). Crystal structure of the γ-secretase component nicastrin. Proc. Natl. Acad. Sci. USA 111, 13349-13354.
57. Zhang, X., Hoey, R. J., Lin, G., Koide, A., Leung, B., Ahn, K., Dolios, G., Paduch, M., Ikeuchi, T., Wang, R. et al. (2012). Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of γ-secretase using synthetic antibodies. Proc. Natl. Acad. Sci. USA 109, 8534-8539.