TY - JOUR
T1 - Presenilin 1 regulates pharmacologically distinct γ-secretase activities
T2 - Implications for the role of presenilin in γ-secretase cleavage
AU - Murphy, M. Paul
AU - Uljon, Sacha N.
AU - Fraser, Paul E.
AU - Fauq, Abdul
AU - Lookingbill, Hilary A.
AU - Findlay, Kirk A.
AU - Smith, Tawnya E.
AU - Lewis, Patrick A.
AU - Chris McLendon, D.
AU - Wang, Rong
AU - Golde, Todd E.
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 2000/8/25
Y1 - 2000/8/25
N2 - Presenilins (PSs) are polytopic membrane proteins that have been implicated as potential therapeutic targets in Alzheimer's disease because of their role in regulating the γ-secretase cleavage that generates the amyloid β protein (Aβ). It is not clear how PSs regulate γ-secretase cleavage, but there is evidence that PSs could be either essential cofactors in the γ-secretase cleavage, γ-secretase themselves, or regulators of intracellular trafficking that indirectly influence γ-secretase cleavage. Using presenilin 1 (PS1) mutants that inhibit Aβ production in conjunction with transmembrane domain mutants of the amyloid protein precursor that are cleaved by pharmacologically distinct γ-secretases, we show that PS1 regulates multiple pharmacologically distinct γ-secretase activities as well as inducible α-secretase activity. It is likely that PS1 acts indirectly to regulate these activities (as in a trafficking or chaperone role), because these data indicate that for PS1 to be γ-secretase it must either have multiple active sites or exist in a variety of catalytically active forms that are altered to an equivalent extent by the mutations we have studied.
AB - Presenilins (PSs) are polytopic membrane proteins that have been implicated as potential therapeutic targets in Alzheimer's disease because of their role in regulating the γ-secretase cleavage that generates the amyloid β protein (Aβ). It is not clear how PSs regulate γ-secretase cleavage, but there is evidence that PSs could be either essential cofactors in the γ-secretase cleavage, γ-secretase themselves, or regulators of intracellular trafficking that indirectly influence γ-secretase cleavage. Using presenilin 1 (PS1) mutants that inhibit Aβ production in conjunction with transmembrane domain mutants of the amyloid protein precursor that are cleaved by pharmacologically distinct γ-secretases, we show that PS1 regulates multiple pharmacologically distinct γ-secretase activities as well as inducible α-secretase activity. It is likely that PS1 acts indirectly to regulate these activities (as in a trafficking or chaperone role), because these data indicate that for PS1 to be γ-secretase it must either have multiple active sites or exist in a variety of catalytically active forms that are altered to an equivalent extent by the mutations we have studied.
UR - http://www.scopus.com/inward/record.url?scp=0034714316&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034714316&partnerID=8YFLogxK
U2 - 10.1074/jbc.M002812200
DO - 10.1074/jbc.M002812200
M3 - Article
C2 - 10816583
AN - SCOPUS:0034714316
SN - 0021-9258
VL - 275
SP - 26277
EP - 26284
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 34
ER -