Moonlighting activity of presenilin in plants is independent of γ-secretase and evolutionary conserved

Abha Khandelwal, Dilip Chandu, Catherine M. Roe, Raphael Kopan, Ralph S. Quatrano

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Presenilins (PS) provide the catalytic activity for γ-secretase, which cleaves physiologically relevant substrates including Notch, ErbB4, and APP. Recent genetic studies indicated that the contribution of PS1 to mouse development includes γ-secretase-independent functions that cannot be easily explained by any of the demonstrated or hypothesized functions of this protein. To begin a nonbiased analysis of PS1 activity unencumbered by the dominant effect stemming from loss of Notch function, we characterized PS functions in the early land plant Physcomitrella patens, which lacks Notch, ErbB4, and APP. Removal of P. patens PS resulted in phenotypic abnormalities. Further assays performed to delineate the defective pathways in PS-deficient P. patens implicated improper function of the cytoskeletal network. Importantly, this characterization of a nonmetazoan PS uncovered a previously undescribed, evolutionarily conserved function (human PS1 can rescue the growth and light responses) that is γ-secretase-independent (mutants with substitutions of the catalytic aspartyl residues retain the activity). Introduction of PpPS into PS-deficient mouse embryonic fibroblasts rescues normal growth rates, demonstrating that at least some metazoan functions of PS are evolutionarily conserved.

Original languageEnglish
Pages (from-to)13337-13342
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number33
DOIs
StatePublished - Aug 14 2007

Keywords

  • Alzheimer's disease
  • Cytoskeleton
  • Evolution
  • Physcomitrella
  • iCLiP

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