Department of Psychiatry, Brudnick Neuropsychiatric Research Institute
Biochemistry, Biophysics, and Structural Biology | Cellular and Molecular Physiology | Mental Disorders | Molecular and Cellular Neuroscience | Nervous System Diseases
The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/PS2) underlie production of beta-amyloid, the key process in Alzheimer's disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the gamma-cleavage activities of PSENs that produce Abeta, but not the epsilon-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 epsilon-like proteolysis. PSEN1 with a G382A or a P433A mutation in evolutionary invariant sites retains functionally important APP epsilon- and Notch S3- cleavage activities, but G382A inhibits APP gamma-cleavage and Abeta production and a P433A elevates Abeta. The G382A variant cannot restore the normal cellular ER Ca(2+) 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) Ca(2+) 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.
regulated intramembrane proteolysis, intramembrane aspartyl proteases, presenilin, IMPAS/SPP, mutational re-modelling
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Copyright: Grigorenko et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
Oncotarget. 2017 May 30;8(47):82006-82026. doi: 10.18632/oncotarget.18299. eCollection 2017 Oct 10. Link to article on publisher's site
Grigorenko, Anastasia P.; Moliaka, Youri K.; Plotnikova, Olga V.; Smirnov, Alexander; Nikishina, Vera A.; Goltsov, Andrey Y.; Gusev, Fedor; Andreeva, Tatiana V.; Nelson, Omar; Bezprozvanny, Ilya; and Rogaev, Evgeny I., "Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer's disease" (2017). Open Access Articles. 3282.
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This work is licensed under a Creative Commons Attribution 3.0 License.
Biochemistry, Biophysics, and Structural Biology Commons, Cellular and Molecular Physiology Commons, Mental Disorders Commons, Molecular and Cellular Neuroscience Commons, Nervous System Diseases Commons