Glu(332) in the Nicastrin ectodomain is essential for gamma-secretase complex maturation but not for its activity - PubMed (original) (raw)
. 2008 Jul 18;283(29):20096-105.
doi: 10.1074/jbc.M803040200. Epub 2008 May 23.
Affiliations
- PMID: 18502756
- DOI: 10.1074/jbc.M803040200
Free article
Glu(332) in the Nicastrin ectodomain is essential for gamma-secretase complex maturation but not for its activity
Lucía Chávez-Gutiérrez et al. J Biol Chem. 2008.
Free article
Abstract
The gamma-secretase complex is responsible for the proteolysis of integral membrane proteins. Nicastrin has been proposed to operate as the substrate receptor of the complex with the glutamate 332 (Glu(333) in human) serving as the anionic binding site for the alpha-amino-terminal group of substrates. The putative binding site is located within the aminopeptidase-like domain of Nicastrin. The Glu(332) is proposed to function as the counterpart of the exopeptidase Glu located in the active site of these peptidases. Although Glu(332) could bind the alpha-amino-terminal group of substrates, we hypothesized, in analogy with M28-aminopeptidases, that other residues in the putative binding site of Nicastrin should participate in the interaction as well. Surprisingly, mutagenesis of these residues affected the in vivo processing of APP and Notch substrates only weakly. In addition, the E332Q mutation, which completely abolishes the anionic alpha-amino-terminal binding function, remained fully active. When we introduced the previously characterized E332A mutation, we found strongly decreased gamma-secretase complex levels, but the remaining complex appeared as active as the wild-type complex. We confirmed in two independent in vitro assays that the specific enzymatic activity of the E332A mutant was comparable with that of the wild-type complex. Thus, Glu(332) crucially affects complex maturation rather than substrate recognition. Moreover other Nicastrin mutants, designed to either impede or alter substantially the putative binding pocket, affected only marginally gamma-secretase activity. Consequently, these studies indicate that the main role of the Glu(332) is in the maturation and assembly of gamma-secretase rather than in the recognition of the substrates.
Similar articles
- Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of γ-secretase using synthetic antibodies.
Zhang X, Hoey RJ, Lin G, Koide A, Leung B, Ahn K, Dolios G, Paduch M, Ikeuchi T, Wang R, Li YM, Koide S, Sisodia SS. Zhang X, et al. Proc Natl Acad Sci U S A. 2012 May 29;109(22):8534-9. doi: 10.1073/pnas.1202691109. Epub 2012 May 14. Proc Natl Acad Sci U S A. 2012. PMID: 22586122 Free PMC article. - Glu-333 of nicastrin directly participates in gamma-secretase activity.
Dries DR, Shah S, Han YH, Yu C, Yu S, Shearman MS, Yu G. Dries DR, et al. J Biol Chem. 2009 Oct 23;284(43):29714-24. doi: 10.1074/jbc.M109.038737. Epub 2009 Sep 3. J Biol Chem. 2009. PMID: 19729449 Free PMC article. - Evidence That the "Lid" Domain of Nicastrin Is Not Essential for Regulating γ-Secretase Activity.
Zhang X, Sullivan E, Scimeca M, Wu X, Li YM, Sisodia SS. Zhang X, et al. J Biol Chem. 2016 Mar 25;291(13):6748-53. doi: 10.1074/jbc.C115.701649. Epub 2016 Feb 17. J Biol Chem. 2016. PMID: 26887941 Free PMC article. - Activity of gamma-secretase on substrates other than APP.
Lleó A. Lleó A. Curr Top Med Chem. 2008;8(1):9-16. doi: 10.2174/156802608783334060. Curr Top Med Chem. 2008. PMID: 18220928 Review. - Gamma-secretase: structure, function, and modulation for Alzheimer's disease.
Wolfe MS. Wolfe MS. Curr Top Med Chem. 2008;8(1):2-8. doi: 10.2174/156802608783334024. Curr Top Med Chem. 2008. PMID: 18220927 Review.
Cited by
- Enzyme-substrate interface targeting by imidazole-based γ-secretase modulators activates γ-secretase and stabilizes its interaction with APP.
Petit D, Hitzenberger M, Koch M, Lismont S, Zoltowska KM, Enzlein T, Hopf C, Zacharias M, Chávez-Gutiérrez L. Petit D, et al. EMBO J. 2022 Nov 2;41(21):e111084. doi: 10.15252/embj.2022111084. Epub 2022 Sep 19. EMBO J. 2022. PMID: 36121025 Free PMC article. - The Genomic Architecture of Hidradenitis Suppurativa-A Systematic Review.
Pace NP, Mintoff D, Borg I. Pace NP, et al. Front Genet. 2022 Mar 23;13:861241. doi: 10.3389/fgene.2022.861241. eCollection 2022. Front Genet. 2022. PMID: 35401657 Free PMC article. Review. - Revisiting APP secretases: an overview on the holistic effects of retinoic acid receptor stimulation in APP processing.
Vitória JJM, Trigo D, da Cruz E Silva OAB. Vitória JJM, et al. Cell Mol Life Sci. 2022 Jan 28;79(2):101. doi: 10.1007/s00018-021-04090-4. Cell Mol Life Sci. 2022. PMID: 35089425 Free PMC article. Review. - TrkA-mediated endocytosis of p75-CTF prevents cholinergic neuron death upon γ-secretase inhibition.
Franco ML, García-Carpio I, Comaposada-Baró R, Escribano-Saiz JJ, Chávez-Gutiérrez L, Vilar M. Franco ML, et al. Life Sci Alliance. 2021 Feb 3;4(4):e202000844. doi: 10.26508/lsa.202000844. Print 2021 Apr. Life Sci Alliance. 2021. PMID: 33536237 Free PMC article. - Super-resolution microscopy reveals majorly mono- and dimeric presenilin1/γ-secretase at the cell surface.
Escamilla-Ayala AA, Sannerud R, Mondin M, Poersch K, Vermeire W, Paparelli L, Berlage C, Koenig M, Chavez-Gutierrez L, Ulbrich MH, Munck S, Mizuno H, Annaert W. Escamilla-Ayala AA, et al. Elife. 2020 Jul 7;9:e56679. doi: 10.7554/eLife.56679. Elife. 2020. PMID: 32631487 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources