We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Identification of an Archaeal Presenilin-Like Intramembrane Protease.
- Authors
Torres-Arancivia, Celia; Ross, Carolyn M.; Chavez, Jose; Assur, Zahra; Dolios, Georgia; Mancia, Filippo; Ubarretxena-Belandia, Iban
- Abstract
Background: The GXGD-type diaspartyl intramembrane protease, presenilin, constitutes the catalytic core of the c-secretase multi-protein complex responsible for activating critical signaling cascades during development and for the production of b-amyloid peptides (Ab) implicated in Alzheimer's disease. The only other known GXGD-type diaspartyl intramembrane proteases are the eukaryotic signal peptide peptidases (SPPs). The presence of presenilin-like enzymes outside eukaryots has not been demonstrated. Here we report the existence of presenilin-like GXGD-type diaspartyl intramembrane proteases in archaea. Methodology and Principal Findings: We have employed in vitro activity assays to show that MCMJR1, a polytopic membrane protein from the archaeon Methanoculleus marisnigri JR1, is an intramembrane protease bearing the signature YD and GXGD catalytic motifs of presenilin-like enzymes. Mass spectrometry analysis showed MCMJR1 could cleave model intramembrane protease substrates at several sites within their transmembrane region. Remarkably, MCMJR1 could also cleave substrates derived from the b-amyloid precursor protein (APP) without the need of protein co-factors, as required by presenilin. Two distinct cleavage sites within the transmembrane domain of APP could be identified, one of which coincided with Ab40, the predominant site processed by c-secretase. Finally, an established presenilin and SPP transition-state analog inhibitor could inhibit MCMJR1. Conclusions and Significance: Our findings suggest that a primitive GXGD-type diaspartyl intramembrane protease from archaea can recapitulate key biochemical properties of eukaryotic presenilins and SPPs. MCMJR1 promises to be a more tractable, simpler system for in depth structural and mechanistic studies of GXGD-type diaspartyl intramembrane proteases.
- Subjects
PRESENILINS; MEMBRANE proteins; PROTEOLYTIC enzymes; SIGNAL peptidases; ALZHEIMER'S disease; BASAL ganglia diseases; DEMENTIA; PRESENILE dementia; ARCHAEBACTERIA
- Publication
PLoS ONE, 2010, Vol 5, Issue 9, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0013072