Mutagenesis mapping of the presenilin 1 calcium leak conductance pore

Omar Nelson, Charlene Supnet, Alexandra Tolia, Katrien Horre, Bart De Strooper, Ilya Bezprozvanny

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Missense mutations in presenilin 1 (PS1) and presenilin 2 (PS2) proteins are a major cause of familial Alzheimer disease. Presenilins are proteins with nine transmembrane (TM) domains that function as catalytic subunits of the γ-secretase complex responsible for the cleavage of the amyloid precursor protein and other type I transmembrane proteins. The waterfilled cavity within presenilin is necessary to mediate the intramembrane proteolysis reaction. Consistent with this idea, cysteine-scanning mutagenesis and NMR studies revealed a number of water-accessible residues within TM7 and TM9 of mouse PS1. In addition to γ-secretase function, presenilins also demonstrate a low conductance endoplasmic reticulum Ca2+ leak function, and many familial Alzheimer disease presenilin mutations impair this function. To map the potential Ca2+ conductance pore in PS1, we systematically evaluated endoplasmic reticulum Ca2+ leak activity supported by a series of cysteine point mutants in TM6, TM7, and TM9 of mouse PS1. The results indicate that TM7 and TM9, but not TM6, could play an important role in forming the conductance pore of PS1. These results are consistent with previous cysteine-scanning mutagenesis and NMR analyses of PS1 and provide further support for our hypothesis that the hydrophilic catalytic cavity of presenilins may also constitute a Ca2+ conductance pore.

Original languageEnglish (US)
Pages (from-to)22339-22347
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number25
DOIs
StatePublished - Jun 24 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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