TY - JOUR
T1 - Mutational re-modeling of di-aspartyl intramembrane proteases
T2 - Uncoupling physiologically-relevant activities from those associated with Alzheimer's disease
AU - Grigorenko, Anastasia P.
AU - Moliaka, Youri K.
AU - Plotnikova, Olga V.
AU - Smirnov, Alexander
AU - Nikishina, Vera A.
AU - Goltsov, Andrey Y.
AU - Gusev, Fedor
AU - Andreeva, Tatiana V.
AU - Nelson, Omar
AU - Bezprozvanny, Ilya
AU - Rogaev, Evgeny I.
N1 - Funding Information:
This work was funded by NIH/NIA AG029360, and in part by NIH/NINDS NS045854, American Alzheimer's Association, Russian Science Foundation #14-44-00077 (in part, C.elegans work) and #14-50-00029 (bioinformatics).
Publisher Copyright:
© Grigorenko et al.
PY - 2017
Y1 - 2017
N2 - The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/ PS2) underlie production of β-amyloid, the key process in Alzheimer's disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the γ-cleavage activities of PSENs that produce Aβ, but not the ε-like cleavage activity that release physiologically essential transcription activators, is a potential approach for the development of rational therapies for AD. In order to identify whether different activities of PSEN1 can be dissociated, we designed multiple mutations in the evolutionary conserved sites of PSEN1. We tested them in vitro and in vivo assays and compared their activities with mutant isoforms of presenilin-related intramembrane di-aspartyl protease (IMPAS1 (IMP1)/signal peptide peptidase (SPP)). PSEN1 autocleavage was more resistant to the mutation remodeling than the ε-like proteolysis. PSEN1 with a G382A or a P433A mutation in evolutionary invariant sites retains functionally important APP ε- and Notch S3- cleavage activities, but G382A inhibits APP γ-cleavage and Aβ production and a P433A elevates Aβ. The G382A variant cannot restore the normal cellular ER Ca2+ leak in PSEN1/PSEN2 double knockout cells, but efficiently rescues the loss-of-function (Egl) phenotype of presenilin in C. elegans. We found that, unlike in PSEN1 knockout cells, endoplasmic reticulum (ER) Ca2+ leak is not changed in the absence of IMP1/SPP. IMP1/SPP with the analogous mutations retained efficiency in cleavage of transmembrane substrates and rescued the lethality of Ce-imp-2 knockouts. In summary, our data show that mutations near the active catalytic sites of intramembrane di-aspartyl proteases have different consequences on proteolytic and signaling functions.
AB - The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/ PS2) underlie production of β-amyloid, the key process in Alzheimer's disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the γ-cleavage activities of PSENs that produce Aβ, but not the ε-like cleavage activity that release physiologically essential transcription activators, is a potential approach for the development of rational therapies for AD. In order to identify whether different activities of PSEN1 can be dissociated, we designed multiple mutations in the evolutionary conserved sites of PSEN1. We tested them in vitro and in vivo assays and compared their activities with mutant isoforms of presenilin-related intramembrane di-aspartyl protease (IMPAS1 (IMP1)/signal peptide peptidase (SPP)). PSEN1 autocleavage was more resistant to the mutation remodeling than the ε-like proteolysis. PSEN1 with a G382A or a P433A mutation in evolutionary invariant sites retains functionally important APP ε- and Notch S3- cleavage activities, but G382A inhibits APP γ-cleavage and Aβ production and a P433A elevates Aβ. The G382A variant cannot restore the normal cellular ER Ca2+ leak in PSEN1/PSEN2 double knockout cells, but efficiently rescues the loss-of-function (Egl) phenotype of presenilin in C. elegans. We found that, unlike in PSEN1 knockout cells, endoplasmic reticulum (ER) Ca2+ leak is not changed in the absence of IMP1/SPP. IMP1/SPP with the analogous mutations retained efficiency in cleavage of transmembrane substrates and rescued the lethality of Ce-imp-2 knockouts. In summary, our data show that mutations near the active catalytic sites of intramembrane di-aspartyl proteases have different consequences on proteolytic and signaling functions.
KW - IMPAS/SPP
KW - Intramembrane aspartyl proteases
KW - Mutational re-modelling
KW - Presenilin
KW - Regulated intramembrane proteolysis
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U2 - 10.18632/oncotarget.18299
DO - 10.18632/oncotarget.18299
M3 - Article
C2 - 29137240
AN - SCOPUS:85030872094
SN - 1949-2553
VL - 8
SP - 82006
EP - 82026
JO - Oncotarget
JF - Oncotarget
IS - 47
ER -