Research Papers:

Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer’s disease

Anastasia P. Grigorenko _, Youri K. Moliaka, Olga V. Plotnikova, Alexander Smirnov, Vera A. Nikishina, Andrey Y. Goltsov, Fedor Gusev, Tatiana V. Andreeva, Omar Nelson, Ilya Bezprozvanny and Evgeny I. Rogaev

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Oncotarget. 2017; 8:82006-82026. https://doi.org/10.18632/oncotarget.18299

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Anastasia P. Grigorenko1,2,3,*, Youri K. Moliaka1,*, Olga V. Plotnikova1, Alexander Smirnov1, Vera A. Nikishina1, Andrey Y. Goltsov2,3, Fedor Gusev2,3, Tatiana V. Andreeva2,3, Omar Nelson4, Ilya Bezprozvanny4 and Evgeny I. Rogaev1,2,3,5

1Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA

2Department of Genomics and Human Genetics, Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991 Russia

3Center for Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia

4Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9040, USA

5Center for Genetics and Genetic Technologies, Faculty of Biology, Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119234, Russia

*These authors have contributed equally to this work

Correspondence to:

Anastasia P. Grigorenko, email: [email protected]

Evgeny I. Rogaev, email: [email protected]

Keywords: regulated intramembrane proteolysis, intramembrane aspartyl proteases, presenilin, IMPAS/SPP, mutational re-modelling

Received: October 04, 2016     Accepted: April 28, 2017     Published: May 30, 2017


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 auto-cleavage 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.

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