PMID- 10206644
OWN - NLM
STAT- MEDLINE
DCOM- 19990428
LR  - 20220331
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 398
IP  - 6727
DP  - 1999 Apr 8
TI  - Two transmembrane aspartates in presenilin-1 required for presenilin
      endoproteolysis and gamma-secretase activity.
PG  - 513-7
AB  - 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.
FAU - Wolfe, M S
AU  - Wolfe MS
AD  - Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's
      Hospital, Boston, Massachusetts 02115, USA. mwolfe@utmem.edu
FAU - Xia, W
AU  - Xia W
FAU - Ostaszewski, B L
AU  - Ostaszewski BL
FAU - Diehl, T S
AU  - Diehl TS
FAU - Kimberly, W T
AU  - Kimberly WT
FAU - Selkoe, D J
AU  - Selkoe DJ
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Coenzymes)
RN  - 0 (Membrane Proteins)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (Peptide Fragments)
RN  - 0 (Presenilin-1)
RN  - 0 (Recombinant Proteins)
RN  - 30KYC7MIAI (Aspartic Acid)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (BACE1 protein, human)
SB  - IM
CIN - Nature. 1999 Apr 8;398(6727):466-7. PMID: 10206639
MH  - Alzheimer Disease/metabolism
MH  - Amyloid Precursor Protein Secretases
MH  - Amyloid beta-Peptides/*metabolism
MH  - Amyloid beta-Protein Precursor/metabolism
MH  - Animals
MH  - Aspartic Acid/*metabolism
MH  - Aspartic Acid Endopeptidases/metabolism
MH  - CHO Cells
MH  - COS Cells
MH  - Cell Line
MH  - Cell Membrane/metabolism
MH  - Cell-Free System
MH  - Coenzymes/metabolism
MH  - Cricetinae
MH  - Electrochemistry
MH  - Endopeptidases/*metabolism
MH  - Exons
MH  - Humans
MH  - Membrane Proteins/chemistry/genetics/*metabolism
MH  - Microsomes/metabolism
MH  - Mutagenesis, Site-Directed
MH  - Peptide Fragments/metabolism
MH  - Presenilin-1
MH  - Protein Folding
MH  - Recombinant Proteins/metabolism
MH  - Transfection
EDAT- 1999/04/17 02:16
MHDA- 2001/03/23 10:01
CRDT- 1999/04/17 02:16
PHST- 1999/04/17 02:16 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/04/17 02:16 [entrez]
AID - 10.1038/19077 [doi]
PST - ppublish
SO  - Nature. 1999 Apr 8;398(6727):513-7. doi: 10.1038/19077.