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PMID: 19036728 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes.

The Journal of biological chemistry ·Vol. 284 ·No. 5 ·2009-01-30 ·Pages 2967-2977

Placanica L, Tarassishin L, Yang G, Peethumnongsin E, Kim SH, Zheng H, Sisodia SS, Li YM

Abstract

gamma-Secretase is known to play a pivotal role in the pathogenesis of Alzheimer disease through production of amyloidogenic Abeta42 peptides. Early onset familial Alzheimer disease mutations in presenilin (PS), the catalytic core of gamma-secretase, invariably increase the Abeta42:Abeta40 ratio. However, the mechanism by which these mutations affect gamma-secretase complex formation and cleavage specificity is poorly understood. We show that our in vitro assay system recapitulates the effect of PS1 mutations on the Abeta42:Abeta40 ratio observed in cell and animal models. We have developed a series of small molecule affinity probes that allow us to characterize active gamma-secretase complexes. Furthermore we reveal that the equilibrium of PS1- and PS2-containing active complexes is dynamic and altered by overexpression of Pen2 or PS1 mutants and that formation of PS2 complexes is positively correlated with increased Abeta42:Abeta40 ratios. These data suggest that perturbations to gamma-secretase complex equilibrium can have a profound effect on enzyme activity and that increased PS2 complexes along with mutated PS1 complexes contribute to an increased Abeta42:Abeta40 ratio.

MeSH Terms
Alzheimer Disease/enzymology,metabolism,physiopathology Amyloid Precursor Protein Secretases/metabolism,physiology Animals Biotin/metabolism Cell Line Flavin-Adenine Dinucleotide/genetics,physiology Gene Knock-In Techniques HeLa Cells Humans Membrane Proteins/physiology Mice Presenilin-1/metabolism,physiology Presenilin-2/metabolism,physiology
Chemicals
Membrane Proteins PSEN2 protein, human PSENEN protein, human Presenilin-1 Presenilin-2 Flavin-Adenine Dinucleotide Biotin Amyloid Precursor Protein Secretases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Placanica Lisa
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065; Department of Pharmacology, Weill Graduate School of Medical Science of Cornell University, New York, New York 10065.
Tarassishin Leonid
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065.
Yang Guangli
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065.
Peethumnongsin Erica
Huffington Center on Aging, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.
Kim Seong-Hun
The Center for Molecular Neurobiology, The University of Chicago, Chicago, Illinois 60637.
Zheng Hui
Huffington Center on Aging, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.
Sisodia Sangram S
The Center for Molecular Neurobiology, The University of Chicago, Chicago, Illinois 60637.
Li Yue-Ming
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065; Department of Pharmacology, Weill Graduate School of Medical Science of Cornell University, New York, New York 10065. Electronic address: liy2@mskcc.org.
References (43)
43 references, click to expand
  1. Gamma-secretase complex assembly within the early secretory pathway.
    J Biol Chem. 2005 Feb 25;280(8):6471-8 PMID: 15591316
  2. The presenilin proteins are components of multiple membrane-bound complexes that have different biological activities.
    J Biol Chem. 2004 Jul 23;279(30):31329-36 PMID: 15123598
  3. Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism.
    Mol Neurodegener. 2007 Feb 08;2:4 PMID: 17288597
  4. TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity.
    Nature. 2006 Apr 27;440(7088):1208-12 PMID: 16641999
  5. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1.
    Nature. 2000 Jun 8;405(6787):689-94 PMID: 10864326
  6. Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression.
    Nat Cell Biol. 2000 Dec;2(12):863-70 PMID: 11146649
  7. Abeta40 inhibits amyloid deposition in vivo.
    J Neurosci. 2007 Jan 17;27(3):627-33 PMID: 17234594
  8. In vitro characterization of the presenilin-dependent gamma-secretase complex using a novel affinity ligand.
    Biochemistry. 2003 Jul 15;42(27):8133-42 PMID: 12846562
  9. CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer's disease amyloid beta-peptide production.
    Proc Natl Acad Sci U S A. 2005 May 24;102(21):7499-504 PMID: 15890777
  10. L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity.
    Biochemistry. 2000 Aug 1;39(30):8698-704 PMID: 10913280
  11. Stereo-controlled synthesis of novel photoreactive gamma-secretase inhibitors.
    Bioorg Med Chem Lett. 2009 Feb 1;19(3):922-5 PMID: 19097779
  12. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state.
    Proc Natl Acad Sci U S A. 2000 May 23;97(11):6138-43 PMID: 10801983
  13. Reconstitution of gamma-secretase activity.
    Nat Cell Biol. 2003 May;5(5):486-8 PMID: 12679784
  14. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.
    Neuron. 1996 Nov;17(5):1005-13 PMID: 8938131
  15. Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities.
    J Biol Chem. 2003 Jun 20;278(25):22475-81 PMID: 12684521
  16. Aph-1 contributes to the stabilization and trafficking of the gamma-secretase complex through mechanisms involving intermolecular and intramolecular interactions.
    J Biol Chem. 2005 Apr 1;280(13):12967-75 PMID: 15644323
  17. The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism.
    Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):403-9 PMID: 17197420
  18. Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40.
    Hum Mutat. 2006 Jul;27(7):686-95 PMID: 16752394
  19. Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors.
    J Biol Chem. 2000 Nov 3;275(44):34086-91 PMID: 10915801
  20. Active gamma-secretase complexes contain only one of each component.
    J Biol Chem. 2007 Nov 23;282(47):33985-93 PMID: 17911105
  21. Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology.
    J Neurosci. 2006 Apr 5;26(14):3845-54 PMID: 16597739
  22. Evidence that CD147 modulation of beta-amyloid (Abeta) levels is mediated by extracellular degradation of secreted Abeta.
    J Biol Chem. 2008 Jul 11;283(28):19489-98 PMID: 18456655
  23. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.
    Nature. 1996 Oct 24;383(6602):710-3 PMID: 8878479
  24. Purification and characterization of the human gamma-secretase complex.
    Biochemistry. 2004 Aug 3;43(30):9774-89 PMID: 15274632
  25. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors.
    J Biol Chem. 1997 Nov 7;272(45):28415-22 PMID: 9353300
  26. Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment heterodimer within the gamma-secretase complex.
    J Biol Chem. 2004 May 28;279(22):23255-61 PMID: 15039426
  27. Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1.
    Nat Cell Biol. 2000 Jul;2(7):428-34 PMID: 10878808
  28. Structure of the catalytic pore of gamma-secretase probed by the accessibility of substituted cysteines.
    J Neurosci. 2006 Nov 15;26(46):12081-8 PMID: 17108181
  29. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1.
    J Biol Chem. 2003 Mar 7;278(10):7850-4 PMID: 12522139
  30. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2.
    Proc Natl Acad Sci U S A. 2003 May 27;100(11):6382-7 PMID: 12740439
  31. Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrate.
    Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2720-5 PMID: 11867728
  32. Identification of distinct gamma-secretase complexes with different APH-1 variants.
    J Biol Chem. 2004 Oct 1;279(40):41340-5 PMID: 15286082
  33. Wild-type presenilin 1 protects against Alzheimer disease mutation-induced amyloid pathology.
    J Biol Chem. 2006 Jun 2;281(22):15330-6 PMID: 16574645
  34. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms.
    J Neurochem. 2006 Feb;96(3):732-42 PMID: 16405513
  35. {gamma}-Secretase Substrate Concentration Modulates the Abeta42/Abeta40 Ratio: IMPLICATIONS FOR ALZHEIMER DISEASE.
    J Biol Chem. 2007 Aug 10;282(32):23639-44 PMID: 17556361
  36. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.
    Nature. 1999 Apr 8;398(6727):513-7 PMID: 10206644
  37. Nicastrin functions as a gamma-secretase-substrate receptor.
    Cell. 2005 Aug 12;122(3):435-47 PMID: 16096062
  38. When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease.
    EMBO Rep. 2007 Feb;8(2):136-40 PMID: 17268504
  39. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex.
    Neuron. 2003 Apr 10;38(1):9-12 PMID: 12691659
  40. Pathological activity of familial Alzheimer's disease-associated mutant presenilin can be executed by six different gamma-secretase complexes.
    Neurobiol Dis. 2007 Jul;27(1):102-7 PMID: 17560791
  41. The role of presenilin cofactors in the gamma-secretase complex.
    Nature. 2003 Mar 27;422(6930):438-41 PMID: 12660785
  42. Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease.
    EMBO Rep. 2007 Feb;8(2):141-6 PMID: 17268505
  43. 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 Nov 5;279(45):46455-63 PMID: 15322109
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M807269200
Email
liy2@mskcc.org
Published
2009-01-30
Epub
2008-00-25
Pages
2967-2977
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2631949
Subset
IM
Grants
NIA NIH HHS · R01-AG20670 · United States
NIA NIH HHS · R01-AG026660 · United States
NCI NIH HHS · T32 CA062948-11A1 · United States
NIGMS NIH HHS · T32 GM073546-01A1 · United States
NIA NIH HHS · R01 AG020670 · United States
External Links
PubMed source DOI: 10.1074/jbc.M807269200 PMC Full Text View journal details
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