Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins

Dun Sheng Yang, Anurag Tandon, Fusheng Chen, Gang Yu, Haung Yu, Shigeki Arawaka, Hiroshi Hasegawa, Monika Duthie, Stephen D. Schmidt, Triprayer V. Ramabhadran, Ralph A. Nixon, Paul M. Mathews, Samuel E. Gandy, Howard T J Mount, Peter St George-Hyslop, Paul E. Fraser

Research output: Contribution to journalArticle

132 Citations (Scopus)

Abstract

Nicastrin is an integral component of the high molecular weight presenilin complexes that control proteolytic processing of the amyloid precursor protein and Notch. We report here that nicastrin is most probably a type 1 transmembrane glycoprotein that is expressed at moderate levels in the brain and in cultured neurons. Immunofluoreseence studies demonstrate that nicastrin is localized in the endoplasmic reticulum, Golgi, and a discrete population of vesicles. Glycosidase analyses reveal that endogenous nicastrin undergoes a conventional, trafficking-dependent maturation process. However, when highly expressed in transfected cells, there is a disproportionate accumulation of the endo-β N-acetylglucosaminidase H-sensitive, immature form, with no significant increase in the levels of the fully mature species. Immunoprecipitation revealed that presenilin-1 interacts preferentially with mature nicastrin, suggesting that correct trafficking and co-localization of the presenilin complex components are essential for activity. These findings demonstrate that trafficking and post-translational modifications of nicastrin are tightly regulated processes that accompany the assembly of the active presenilin complexes that execute γ-secretase cleavage. These results also underscore the caveat that simple overexpression of nicastrin in transfected cells may result in the accumulation of large amounts of the immature protein, which is apparently unable to assemble into the active complexes capable of processing amyloid precursor protein and Notch.

Original languageEnglish (US)
Pages (from-to)28135-28142
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number31
DOIs
StatePublished - Aug 2 2002

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Presenilins
Glycosylation
Amyloid beta-Protein Precursor
Presenilin-1
Acetylglucosaminidase
Amyloid Precursor Protein Secretases
Glycoside Hydrolases
Post Translational Protein Processing
Processing
Immunoprecipitation
Endoplasmic Reticulum
Neurons
Brain
Glycoproteins
Molecular Weight
Molecular weight
Population
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Yang, D. S., Tandon, A., Chen, F., Yu, G., Yu, H., Arawaka, S., ... Fraser, P. E. (2002). Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins. Journal of Biological Chemistry, 277(31), 28135-28142. https://doi.org/10.1074/jbc.M110871200

Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins. / Yang, Dun Sheng; Tandon, Anurag; Chen, Fusheng; Yu, Gang; Yu, Haung; Arawaka, Shigeki; Hasegawa, Hiroshi; Duthie, Monika; Schmidt, Stephen D.; Ramabhadran, Triprayer V.; Nixon, Ralph A.; Mathews, Paul M.; Gandy, Samuel E.; Mount, Howard T J; George-Hyslop, Peter St; Fraser, Paul E.

In: Journal of Biological Chemistry, Vol. 277, No. 31, 02.08.2002, p. 28135-28142.

Research output: Contribution to journalArticle

Yang, DS, Tandon, A, Chen, F, Yu, G, Yu, H, Arawaka, S, Hasegawa, H, Duthie, M, Schmidt, SD, Ramabhadran, TV, Nixon, RA, Mathews, PM, Gandy, SE, Mount, HTJ, George-Hyslop, PS & Fraser, PE 2002, 'Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins', Journal of Biological Chemistry, vol. 277, no. 31, pp. 28135-28142. https://doi.org/10.1074/jbc.M110871200
Yang, Dun Sheng ; Tandon, Anurag ; Chen, Fusheng ; Yu, Gang ; Yu, Haung ; Arawaka, Shigeki ; Hasegawa, Hiroshi ; Duthie, Monika ; Schmidt, Stephen D. ; Ramabhadran, Triprayer V. ; Nixon, Ralph A. ; Mathews, Paul M. ; Gandy, Samuel E. ; Mount, Howard T J ; George-Hyslop, Peter St ; Fraser, Paul E. / Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 31. pp. 28135-28142.
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