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Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.
Nature. 1999 Apr 08; 398(6727):513-7.Nat

Abstract

Accumulation of the amyloid-beta protein (Abeta) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease. The final step in the generation of Abeta from the beta-amyloid precursor protein is an apparently intramembranous proteolysis by the elusive gamma-secretase(s). The most common cause of familial Alzheimer's disease is mutation of the genes encoding presenilins 1 and 2, which alters gamma-secretase activity to increase the production of the highly amyloidogenic Abeta42 isoform. Moreover, deletion of presenilin-1 in mice greatly reduces gamma-secretase activity, 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 Abeta production and increases the amounts of the carboxy-terminal fragments of beta-amyloid precursor protein that are the substrates of gamma-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 cleavage, the Asp 385 --> Ala mutation still inhibited gamma-secretase activity. Our results indicate that the two transmembrane aspartate residues are critical for both presenilin-1 endoproteolysis and gamma-secretase activity, and suggest that presenilin 1 is either a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase, an autoactivated intramembranous aspartyl protease.

Authors+Show Affiliations

Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. mwolfe@utmem.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10206644

Citation

Wolfe, M S., et al. "Two Transmembrane Aspartates in Presenilin-1 Required for Presenilin Endoproteolysis and Gamma-secretase Activity." Nature, vol. 398, no. 6727, 1999, pp. 513-7.
Wolfe MS, Xia W, Ostaszewski BL, et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999;398(6727):513-7.
Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., & Selkoe, D. J. (1999). Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature, 398(6727), 513-7.
Wolfe MS, et al. Two Transmembrane Aspartates in Presenilin-1 Required for Presenilin Endoproteolysis and Gamma-secretase Activity. Nature. 1999 Apr 8;398(6727):513-7. PubMed PMID: 10206644.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. AU - Wolfe,M S, AU - Xia,W, AU - Ostaszewski,B L, AU - Diehl,T S, AU - Kimberly,W T, AU - Selkoe,D J, PY - 1999/4/17/pubmed PY - 2001/3/23/medline PY - 1999/4/17/entrez SP - 513 EP - 7 JF - Nature JO - Nature VL - 398 IS - 6727 N2 - Accumulation of the amyloid-beta protein (Abeta) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease. The final step in the generation of Abeta from the beta-amyloid precursor protein is an apparently intramembranous proteolysis by the elusive gamma-secretase(s). The most common cause of familial Alzheimer's disease is mutation of the genes encoding presenilins 1 and 2, which alters gamma-secretase activity to increase the production of the highly amyloidogenic Abeta42 isoform. Moreover, deletion of presenilin-1 in mice greatly reduces gamma-secretase activity, 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 Abeta production and increases the amounts of the carboxy-terminal fragments of beta-amyloid precursor protein that are the substrates of gamma-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 cleavage, the Asp 385 --> Ala mutation still inhibited gamma-secretase activity. Our results indicate that the two transmembrane aspartate residues are critical for both presenilin-1 endoproteolysis and gamma-secretase activity, and suggest that presenilin 1 is either a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase, an autoactivated intramembranous aspartyl protease. SN - 0028-0836 UR - https://www.unboundmedicine.com/medline/citation/10206644/Two_transmembrane_aspartates_in_presenilin_1_required_for_presenilin_endoproteolysis_and_gamma_secretase_activity_ L2 - https://doi.org/10.1038/19077 DB - PRIME DP - Unbound Medicine ER -