Specific domains in anterior pharynx-defective 1 determine its intramembrane interactions with nicastrin and presenilin

Po-Min Chiang, Ryan R. Fortna, Donald L. Price, Tong Li, Philip C. Wong

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

γ-Secretase, a multisubunit transmembrane protease comprised of presenilin, nicastrin, presenilin enhancer 2, and anterior pharynx-defective one, participates in the regulated intramembrane proteolysis of Type I membrane proteins including the amyloid precursor protein (APP). Although Aph-1 is thought to play a structural role in the assembly of γ-secretase complex and several transmembrane domains (TMDs) of Aph-1 have been shown to be critical for its function, the importance of the other domains of Aph-1 remains elusive. We screened a series of Aph-1 mutants and focused on nine mutations distributed in six different TMDs of human APH-1aS, assessing their ability to complement mouse embryonic fibroblasts lacking Aph-1. We showed that mutations in TMD4 (G126) and TMD5 (H171) of Aph-1aS prevented the formation of the Nct/Aph-1 subcomplex. Importantly, although mutations in TMD3 (Q83/E84/R85) and TMD6 (H197) of APH-1aS did not affect Nct/Aph-1 subcomplex formation, both mutations prevented further association/endoproteolysis of PS1. We propose a model that identifies critical TMDs of Aph-1 for associations with Nct and PS for the stepwise assembly of γ-secretase components.

Original languageEnglish
Pages (from-to)277-285
Number of pages9
JournalNeurobiology of Aging
Volume33
Issue number2
DOIs
Publication statusPublished - 2012 Feb 1

Fingerprint

Presenilins
Pharynx
Amyloid Precursor Protein Secretases
Mutation
Presenilin-2
Amyloid beta-Protein Precursor
Proteolysis
Membrane Proteins
Peptide Hydrolases
Fibroblasts

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Chiang, Po-Min ; Fortna, Ryan R. ; Price, Donald L. ; Li, Tong ; Wong, Philip C. / Specific domains in anterior pharynx-defective 1 determine its intramembrane interactions with nicastrin and presenilin. In: Neurobiology of Aging. 2012 ; Vol. 33, No. 2. pp. 277-285.
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Specific domains in anterior pharynx-defective 1 determine its intramembrane interactions with nicastrin and presenilin. / Chiang, Po-Min; Fortna, Ryan R.; Price, Donald L.; Li, Tong; Wong, Philip C.

In: Neurobiology of Aging, Vol. 33, No. 2, 01.02.2012, p. 277-285.

Research output: Contribution to journalArticle

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