Selkoe, Dennis J

Publication Detail

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Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and gamma-secretase activity.

A L Brunkan; M Martinez; J Wang; E S Walker; D Beher; M S Shearman; A M Goate (Profiled Author: Goate, Alison M)

Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Journal of neurochemistry 2005;94(5):1315-28.

Presenilins (PS) are thought to contain the active site for presenilinase endoproteolysis of PS and gamma-secretase cleavage of substrates. The structural requirements for PS incorporation into the gamma-secretase enzyme complex, complex stability and maturation, and appropriate presenilinase and gamma-secretase activity are poorly understood. We used rescue assays to identify sequences in transmembrane domain one (TM1) of PS1 required to support presenilinase and gamma-secretase activities. Swap mutations identified an N-terminal TM1 domain that is important for gamma-secretase activity only and a C-terminal TM1 domain that is essential for both presenilinase and gamma-secretase activities. Exchange of residues 95-98 of PS1 (sw95-98) completely abolishes both activities while the familial Alzheimer's disease mutation V96F significantly inhibits both activities. Reversion of residue 96 back to valine in the sw95-98 mutant rescues PS function, identifying V96 as the critical residue in this region. The TM1 mutants do not bind to an aspartyl protease transition state analog gamma-secretase inhibitor, indicating a conformational change induced by the mutations that abrogates catalytic activity. TM1 mutant PS1 molecules retain the ability to interact with gamma-secretase substrates and gamma-secretase complex members, although Nicastrin stability is decreased by the presence of these mutants. gamma-Secretase complexes that contain V96F mutant PS1 molecules display a partial loss of function for gamma-secretase that alters the ratio of amyloid-beta peptide species produced, leading to the amyloid-beta peptide aggregation that causes familial Alzheimer's disease.

1 Originating Grant

• 1.

  Goate, Alison M

  ROLE OF PRESENILIN IN NOTCH AND APP MATURATION

  30 September 1999 - 31 July 2005

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 1,341,635

Scientific Context

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