Journal Mobile Options
Table of Contents
Vol. 3, No. 4-5, 2006
Issue release date: October 2006
Neurodegenerative Dis 2006;3:275–283
(DOI:10.1159/000095267)

Assembly, Trafficking and Function of γ-Secretase

Kaether C. · Haass C. · Steiner H.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

γ-Secretase catalyzes the final cleavage of the β-amyloid precursor protein to generate amyloid-β peptide, the principal component of amyloid plaques in the brains of patients suffering from Alzheimer’s disease. Here, we review the identification of γ-secretase as a protease complex and its assembly and trafficking to its site(s) of cellular function. In reconstitution experiments, γ-secretase was found to be composed of four integral membrane proteins, presenilin (PS), nicastrin (NCT), PEN-2 and APH-1 that are essential and sufficient for γ-secretase activity. PS, which serves as a catalytic subunit of γ-secretase, was identified as a prototypic member of novel aspartyl proteases of the GxGD type. In human cells, γ-secretase could be further defined as a heterogeneous activity consisting of distinct complexes that are composed of PS1 or PS2 and APH-1a or APH-1b homologues together with NCT and PEN-2. Using green fluorescent protein as a reporter we localized PS and γ-secretase activity at the plasma membrane and endosomes. Investigation of γ-secretase complex assembly in knockdown and knockout cells of the individual subunits allowed us to develop a model of complex assembly in which NCT and APH-1 first stabilize PS before PEN-2 assembles as the last component. Furthermore, we could map domains in PS and PEN-2 that govern assembly and trafficking of the complex. Finally, Rer1 was identified as a PEN-2-binding protein that serves a role as an auxiliary factor for γ-secretase complex assembly.



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297:353–356.
  2. Haass C: Take five-BACE and the gamma-secretase quartet conduct Alzheimer’s amyloid beta-peptide generation. EMBO J 2004;23:483–488.
  3. Steiner H: Uncovering gamma-secretase. Curr Alzheimer Res 2004;1:175–181.
  4. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, et al: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995;375:754–760.
  5. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al: 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 1995;376:775–778.
  6. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, et al: Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 1995;269:973–977.
  7. Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL, Bird TD, Schellenberg GD: A familial Alzheimer’s disease locus on chromosome 1. Science 1995;269:970–973.
  8. Laudon H, Hansson EM, Melen K, Bergman A, Farmery MR, Winblad B, Lendahl U, von Heijne G, Naslund J: A nine-transmembrane domain topology for presenilin 1. J Biol Chem 2005;280:35352–35360.
  9. Oh YS, Turner RJ: Evidence that the COOH terminus of human presenilin 1 is located in extracytoplasmic space. Am J Physiol Cell Physiol 2005;289:C576–581.

    External Resources

  10. Henricson A, Kall L, Sonnhammer EL: A novel transmembrane topology of presenilin based on reconciling experimental and computational evidence. FEBS J 2005;272:2727–2733.
  11. Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS: Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 1996;17:181–190.
  12. Levitan D, Greenwald I: Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 1995;377:351–354.
  13. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S: Secreted amyloid beta-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 1996;2:864–870.
  14. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F: Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998;391:387–390.
  15. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ: Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 1999;398:513–517.
  16. Wolfe MS, Xia W, Moore CL, Leatherwood DD, Ostaszewski B, Rahmati T, Donkor IO, Selkoe DJ: Peptidomimetic probes and molecular modeling suggest that Alzheimer’s gamma-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry 1999;38:4720–4727.
  17. Steiner H, Duff K, Capell A, Romig H, Grim MG, Lincoln S, Hardy J, Yu X, Picciano M, Fechteler K, Citron M, Kopan R, Pesold B, Keck S, Baader M, Tomita T, Iwatsubo T, Baumeister R, Haass C: A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and notch signaling. J Biol Chem 1999;274:28669–28673.
  18. Leimer U, Lun K, Romig H, Walter J, Grunberg J, Brand M, Haass C: Zebrafish (Danio rerio) presenilin promotes aberrant amyloid beta- peptide production and requires a critical aspartate residue for its function in amyloidogenesis. Biochemistry 1999;38:13602–13609.
  19. Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelli JG, Register RB, Sardana MK, Shearman MS, Smith AL, Shi XP, Yin KC, Shafer JA, Gardell SJ: Photoactivated g-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 2000;405:689–694.
  20. Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai JY, Rahmati T, Xia W, Selkoe DJ, Wolfe MS: Transition-state analogue inhibitors of g-secretase bind directly to presenilin-1. Nature Cell Biol 2000;2:428–433.
  21. Steiner H, Kostka M, Romig H, Basset G, Pesold B, Hardy J, Capell A, Meyn L, Grim MG, Baumeister R, Fechteler K, Haass C: Glycine 384 is required for presenilin-1 function and is conserved in polytopic bacterial aspartyl proteases. Nature Cell Biol 2000;2:848–851.
  22. LaPointe CF, Taylor RK: The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases. J Biol Chem 2000;275:1502–1510.
  23. Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B: Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 2002;296:2215–2218.
  24. Krawitz P, Haffner C, Fluhrer R, Steiner H, Schmid B, Haass C: Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenilin homologues SPPL2b and SPPL3. J Biol Chem 2005;280:39515–39523.
  25. Haass C, Steiner H: Alzheimer disease gamma-secretase: a complex story of GxGD-type presenilin proteases. Trends Cell Biol 2002;12:556–562.
  26. Seeger M, Nordstedt C, Petanceska S, Kovacs DM, Gouras GK, Hahne S, Fraser P, Levesque L, Czernik AJ, George-Hyslop PS, Sisodia SS, Thinakaran G, Tanzi RE, Greengard P, Gandy S: Evidence for phosphorylation and oligomeric assembly of presenilin 1. Proc Natl Acad Sci USA 1997;94:5090–5094.
  27. Capell A, Grunberg J, Pesold B, Diehlmann A, Citron M, Nixon R, Beyreuther K, Selkoe DJ, Haass C: 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 1998;273:3205–3211.
  28. Yu G, Chen F, Levesque G, Nishimura M, Zhang DM, Levesque L, Rogaeva E, Xu D, Liang Y, Duthie M, St George-Hyslop PH, Fraser PE: The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains b-catenin. J Biol Chem 1998;273:16470–16475.
  29. Li YM, Lai MT, Xu M, Huang Q, DiMuzio-Mower J, Sardana MK, Shi XP, Yin KC, Shafer JA, Gardell SJ: Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc Natl Acad Sci USA 2000;97:6138–6143.
  30. Thinakaran G, Harris CL, Ratovitski T, Davenport F, Slunt HH, Price DL, Borchelt DR, Sisodia SS: Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem 1997;272:28415–28422.
  31. Steiner H, Capell A, Pesold B, Citron M, Kloetzel PM, Selkoe DJ, Romig H, Mendla K, Haass C: Expression of Alzheimer’s disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation. J Biol Chem 1998;273:32322–32331.
  32. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P: Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000;407:48–54.
  33. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M, Maxwell M, Hai B, Ellis MC, Parks AL, Xu W, Li J, Gurney M, Myers RL, Himes CS, Hiebsch R, Ruble C, Nye JS, Curtis D: Aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 2002;3:85–97.
  34. Goutte C, Tsunozaki M, Hale VA, Priess JR: APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci USA 2002;99:775–779.
  35. Steiner H, Winkler E, Edbauer D, Prokop S, Basset G, Yamasaki A, Kostka M, Haass C: PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. J Biol Chem 2002;277:39062–39065.
  36. Lee SF, Shah S, Li H, Yu C, Han W, Yu G: Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch. J Biol Chem 2002;277:45013–45019.
  37. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C: Reconstitution of gamma-secretase activity. Nat Cell Biol 2003;5:486–488.
  38. Kim SH, Ikeuchi T, Yu C, Sisodia SS: Regulated hyperaccumulation of presenilin-1 and the ‘gamma-secretase’ complex. Evidence for differential intramembranous processing of transmembrane subatrates. J Biol Chem 2003;278:33992–34002.
  39. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ: Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci USA 2003;100:6382–6387.
  40. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T: The role of presenilin cofactors in the gamma-secretase complex. Nature 2003;422:438–441.
  41. Shirotani K, Edbauer D, Kostka M, Steiner H, Haass C: Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin: identification of nicastrin mutants that selectively interact with APH-1. J Neurochem 2004;89:1520–1527.
  42. Hebert SS, Serneels L, Dejaegere T, Horre K, Dabrowski M, Baert V, Annaert W, Hartmann D, De Strooper B: Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol Dis 2004;17:260–272.
  43. Kovacs DM, Fausett HJ, Page KJ, Kim TW, Moir RD, Merriam DE, Hollister RD, Hallmark OG, Mancini R, Felsenstein KM, Hyman BT, Tanzi RE, Wasco W: Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nat Med 1996;2:224–229.
  44. Pasternak SH, Callahan JW, Mahuran DJ: The role of the endosomal/lysosomal system in amyloid-beta production and the pathophysiology of Alzheimer’s disease: reexamining the spatial paradox from a lysosomal perspective. J Alzheimers Dis 2004;6:53–65.
  45. Annaert W, De Strooper B: Presenilins: molecular switches between proteolysis and signal transduction. Trends Neurosci 1999;22:439–443.
  46. Kaether C, Lammich S, Edbauer D, Ertl M, Rietdorf J, Capell A, Steiner H, Haass C: Presenilin-1 affects trafficking and processing of betaAPP and is targeted in a complex with nicastrin to the plasma membrane. J Cell Biol 2002;158:551–561.
  47. Chyung JH, Raper DM, Selkoe DJ: Gamma-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage. J Biol Chem 2005;280:4383–4392.
  48. Pasternak SH, Bagshaw RD, Guiral M, Zhang S, Ackerley CA, Pak BJ, Callahan JW, Mahuran DJ: Presenilin-1, nicastrin, amyloid precursor protein, and gamma-secretase activity are co-localized in the lysosomal membrane. J Biol Chem 2003;278:26687–26694.
  49. Kaether C, Schmitt S, Willem M, Haass C: APP and Notch intracellular domains are generated after transport of their precursors to the cell surface. Traffic 2006, in press.
  50. Edbauer D, Winkler E, Haass C, Steiner H: Presenilin and nicastrin regulate each other and determine amyloid beta -peptide production via complex formation. Proc Natl Acad Sci USA 2002;99:8666–8671.
  51. Prokop S, Shirotani K, Edbauer D, Haass C, Steiner H: Requirement of PEN-2 for stabilization of the presenilin NTF/CTF heterodimer within the gamma-secretase complex. J Biol Chem 2004;279:23255–23261.
  52. Shirotani K, Edbauer D, Capell A, Schmitz J, Steiner H, Haass C: Gamma-secretase activity is associated with a conformational change of nicastrin. J Biol Chem 2003;278:16474–16477.
  53. Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, Thinakaran G, Kim TW, Yu G, Xu H: PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem 2003;278:7850–7854.
  54. Leem JY, Vijayan S, Han P, Cai D, Machura M, Lopes KO, Veselits ML, Xu H, Thinakaran G: Presenilin 1 is required for maturation and cell surface accumulation of nicastrin. J Biol Chem 2002;277:19236–19240.
  55. Edbauer D, Kaether C, Steiner H, Haass C: Co-expression of nicastrin and presenilin rescues a loss of function mutant of APH-1. J Biol Chem 2004;279:37311–37315.
  56. Lee SF, Shah S, Yu C, Wigley WC, Li H, Lim M, Pedersen K, Han W, Thomas P, Lundkvist J, Hao YH, Yu G: A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex. J Biol Chem 2004;279:4144–4152.
  57. Prokop S, Haass C, Steiner H: Length and overall sequence of the PEN-2 C-terminal domain determines its function in the stabilization of presenilin fragments. J Neurochem 2005;94:57–62.
  58. Hasegawa H, Sanjo N, Chen F, Gu YJ, Shier C, Petit A, Kawarai T, Katayama T, Schmidt SD, Mathews PM, Schmitt-Ulms G, Fraser PE, St George-Hyslop P: Both the sequence and length of the C terminus of PEN-2 are critical for intermolecular interactions and function of presenilin complexes. J Biol Chem 2004;279:46455–46463.
  59. Kim SH, Yin YI, Li YM, Sisodia SS: Evidence that assembly of an active gamma-secretase complex occurs in the early compartments of the secretory pathway. J Biol Chem 2004;279:48615–48619.
  60. Capell A, Kaether C, Edbauer D, Shirotani K, Merkl S, Steiner H, Haass C: Nicastrin interacts with gamma-secretase complex components via the N-terminal part of its transmembrane domain. J Biol Chem 2003;278:52519–52523.
  61. Morais VA, Crystal AS, Pijak DS, Carlin D, Costa J, Lee VM, Doms RW: The transmembrane domain region of nicastrin mediates direct interactions with APH-1 and the gamma-secretase complex. J Biol Chem 2003;278:43284–43291.
  62. Kaether C, Capell A, Edbauer D, Winkler E, Novak B, Steiner H, Haass C: The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity. EMBO J 2004;23:4738–4748.
  63. Bergman A, Laudon H, Winblad B, Lundkvist J, Naslund J: The extreme C terminus of presenilin 1 is essential for gamma-secretase complex assembly and activity. J Biol Chem 2004;279:45564–45572.
  64. Kim SH, Sisodia SS: Evidence that the ‘NF’ motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2. J Biol Chem 2005;280:41953–41966.
  65. Watanabe N, Tomita T, Sato C, Kitamura T, Morohashi Y, Iwatsubo T: Pen-2 is incorporated into the gamma-secretase complex through binding to transmembrane domain 4 of presenilin 1. J Biol Chem 2005;280:41967–41975.
  66. Capell A, Beher D, Prokop S, Steiner H, Kaether C, Shearman MS, Haass C: Gamma-secretase complex assembly within the early secretory pathway. J Biol Chem 2005;280:6471–6478.
  67. Sato K, Sato M, Nakano A: Rer1p, a retrieval receptor for ER membrane proteins, recognizes transmembrane domains in multiple modes. Mol Biol Cell 2003;14:3605–3616.
  68. Füllekrug J, Boehm J, Rottger S, Nilsson T, Mieskes G, Schmitt HD: Human Rer1 is localized to the Golgi apparatus and complements the deletion of the homologous Rer1 protein of Saccharomyces cerevisiae. Eur J Cell Biol 1997;74:31–40.
  69. Brunkan AL, Goate AM: Presenilin function and gamma-secretase activity. J Neurochem 2005;93:769–792.
  70. Baumeister R, Leimer U, Zweckbronner I, Jakubek C, Grunberg J, Haass C: Human presenilin-1, but not familial Alzheimer’s disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct 1997;1:149–159.
  71. Steiner H, Romig H, Grim MG, Philipp U, Pesold B, Citron M, Baumeister R, Haass C: The biological and pathological function of the presenilin-1delta exon 9 mutation is independent of its defect to undergo proteolytic processing. J Biol Chem 1999;274:7615–7618.
  72. Capell A, Steiner H, Romig H, Keck S, Baader M, Grim MG, Baumeister R, Haass C: Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch. Nature Cell Biol 2000;2:205–211.
  73. Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, Iwatsubo T, Kudo T, Takeda M, Haass C: Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J 2002;21:5408–5416.
  74. Lammich S, Okochi M, Takeda M, Kaether C, Capell A, Zimmer AK, Edbauer D, Walter J, Steiner H, Haass C: 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 2002;277:44754–44759.
  75. Lleo A, Waldron E, von Arnim CA, Herl L, Tangredi MM, Peltan ID, Strickland DK, Koo EH, Hyman BT, Pietrzik CU, Berezovska O: Low density lipoprotein receptor-related protein (LRP) interacts with presenilin 1 and is a competitive substrate of the amyloid precursor protein (APP) for gamma-secretase. J Biol Chem 2005;280:27303–27309.
  76. Struhl G, Adachi A: Requirements for presenilin-dependent cleavage of Notch and other transmembrane proteins. Mol Cell 2000;6:625–636.
  77. Shah S, Lee SF, Tabuchi K, Hao YH, Yu C, LaPlant Q, Ball H, Dann CE, 3rd, Sudhof T, Yu G: Nicastrin functions as a gamma-secretase-substrate receptor. Cell 2005;122:435–447.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50