Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

1999-04

AUTHORS

Michael S. Wolfe, Weiming Xia, Beth L. Ostaszewski, Thekla S. Diehl, W. Taylor Kimberly, Dennis J. Selkoe

ABSTRACT

Accumulation of the amyloid-β protein (Aβ) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease. The final step in the generation of Aβ from the β-amyloid precursor protein is an apparently intramembranous proteolysis by the elusive γ-secretase(s)1. The most common cause of familial Alzheimer's disease is mutation of the genes encoding presenilins 1 and 2, which alters γ-secretase activity to increase the production of the highly amyloidogenic Aβ42 isoform2. Moreover, deletion of presenilin-1 in mice greatly reduces γ-secretase activity3, indicating that presenilin-1 mediates most of this proteolytic event. Here we report that mutation of either of two conserved transmembrane (TM) aspartate residues in presenilin-1, Asp 257 (in TM6) and Asp 385 (in TM7), substantially reduces Aβ production and increases the amounts of the carboxy-terminal fragments of β-amyloid precursor protein that are the substrates of γ-secretase. We observed these effects in three different cell lines as well as in cell-free microsomes. Either of the Asp → Ala mutations also prevented the normal endoproteolysis of presenilin-1 in the TM6 → TM7 cytoplasmic loop. In a functional presenilin-1 variant (carrying a deletion in exon 9) that is associated with familial Alzheimer's disease and which does not require this cleavage4, the Asp 385 → Ala mutation still inhibited γ-secretase activity. Our results indicate that the two transmembrane aspartate residues are critical for both presenilin-1 endoproteolysis and γ-secretase activity, and suggest that presenilin 1 is either a unique diaspartyl cofactor for γ-secretase or is itself γ-secretase, an autoactivated intramembranous aspartyl protease. More... »

PAGES

513-517

Journal

TITLE

Nature

ISSUE

6727

VOLUME

398

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/19077

    DOI

    http://dx.doi.org/10.1038/19077

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1004359799

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/10206644


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