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, Evgeny I. Rogaev

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)82006-82026
Number of pages21
JournalOncotarget
Volume8
Issue number47
DOIs
StatePublished - 2017

Fingerprint

Aspartic Acid Proteases
Presenilins
Alzheimer Disease
Mutation
Endoplasmic Reticulum
Catalytic Domain
Amyloid
Proteolysis
Protein Isoforms
Efficiency
Phenotype
signal peptide peptidase
Neoplasms

Keywords

  • IMPAS/SPP
  • Intramembrane aspartyl proteases
  • Mutational re-modelling
  • Presenilin
  • Regulated intramembrane proteolysis

ASJC Scopus subject areas

  • Oncology

Cite this

Grigorenko, A. P., Moliaka, Y. K., Plotnikova, O. V., Smirnov, A., Nikishina, V. A., Goltsov, A. Y., ... Rogaev, E. I. (2017). Mutational re-modeling of di-aspartyl intramembrane proteases: Uncoupling physiologically-relevant activities from those associated with Alzheimer's disease. Oncotarget, 8(47), 82006-82026. https://doi.org/10.18632/oncotarget.18299

Mutational re-modeling of di-aspartyl intramembrane proteases : Uncoupling physiologically-relevant activities from those associated with Alzheimer's disease. / 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; Rogaev, Evgeny I.

In: Oncotarget, Vol. 8, No. 47, 2017, p. 82006-82026.

Research output: Contribution to journalArticle

Grigorenko, AP, Moliaka, YK, Plotnikova, OV, Smirnov, A, Nikishina, VA, Goltsov, AY, Gusev, F, Andreeva, TV, Nelson, O, Bezprozvanny, I & Rogaev, EI 2017, 'Mutational re-modeling of di-aspartyl intramembrane proteases: Uncoupling physiologically-relevant activities from those associated with Alzheimer's disease', Oncotarget, vol. 8, no. 47, pp. 82006-82026. https://doi.org/10.18632/oncotarget.18299
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 ; Rogaev, Evgeny I. / Mutational re-modeling of di-aspartyl intramembrane proteases : Uncoupling physiologically-relevant activities from those associated with Alzheimer's disease. In: Oncotarget. 2017 ; Vol. 8, No. 47. pp. 82006-82026.
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