PMID- 10878808
OWN - NLM
STAT- MEDLINE
DCOM- 20000921
LR  - 20101118
IS  - 1465-7392 (Print)
IS  - 1465-7392 (Linking)
VI  - 2
IP  - 7
DP  - 2000 Jul
TI  - Transition-state analogue inhibitors of gamma-secretase bind directly to 
      presenilin-1.
PG  - 428-34
AB  - The beta-amyloid precursor protein (beta-APP), which is involved in the 
      pathogenesis of Alzheimer's disease, and the Notch receptor, which is responsible 
      for critical signalling events during development, both undergo unusual 
      proteolysis within their transmembrane domains by unknown gamma-secretases. Here 
      we show that an affinity reagent designed to interact with the active site of 
      gamma-secretase binds directly and specifically to heterodimeric forms of 
      presenilins, polytopic proteins that are mutated in hereditary Alzheimer's and 
      are known mediators of gamma-secretase cleavage of both beta-APP and Notch. These 
      results provide evidence that heterodimeric presenilins contain the active site 
      of gamma-secretase, and validate presenilins as principal targets for the design 
      of drugs to treat and prevent Alzheimer's disease.
FAU - Esler, W P
AU  - Esler WP
AD  - Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's 
      Hospital, Boston, Massachusetts, 02115, USA.
FAU - Kimberly, W T
AU  - Kimberly WT
FAU - Ostaszewski, B L
AU  - Ostaszewski BL
FAU - Diehl, T S
AU  - Diehl TS
FAU - Moore, C L
AU  - Moore CL
FAU - Tsai, J Y
AU  - Tsai JY
FAU - Rahmati, T
AU  - Rahmati T
FAU - Xia, W
AU  - Xia W
FAU - Selkoe, D J
AU  - Selkoe DJ
FAU - Wolfe, M S
AU  - Wolfe MS
LA  - eng
GR  - AG12749/AG/NIA NIH HHS/United States
GR  - NS37537/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nat Cell Biol
JT  - Nature cell biology
JID - 100890575
RN  - 0 (Affinity Labels)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Membrane Proteins)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (PSEN2 protein, human)
RN  - 0 (Peptide Fragments)
RN  - 0 (Presenilin-1)
RN  - 0 (Presenilin-2)
RN  - 0 (Protease Inhibitors)
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 - Nat Cell Biol. 2002 May;4(5):E110-1; author reply E111-2. PMID: 11988746
MH  - Affinity Labels
MH  - Alzheimer Disease/drug therapy/enzymology
MH  - Amyloid Precursor Protein Secretases
MH  - Amyloid beta-Peptides/metabolism
MH  - Amyloid beta-Protein Precursor/genetics/metabolism
MH  - Animals
MH  - Aspartic Acid Endopeptidases
MH  - CHO Cells
MH  - Cricetinae
MH  - Dimerization
MH  - Endopeptidases/*metabolism
MH  - Humans
MH  - Membrane Proteins/chemistry/*metabolism
MH  - Microsomes/chemistry/metabolism
MH  - Molecular Weight
MH  - Peptide Fragments/chemistry/metabolism
MH  - Presenilin-1
MH  - Presenilin-2
MH  - Protease Inhibitors/*chemistry/*metabolism/pharmacology/therapeutic use
MH  - Protein Binding
MH  - Protein Processing, Post-Translational
MH  - Transfection
EDAT- 2000/07/06 11:00
MHDA- 2000/09/23 11:01
CRDT- 2000/07/06 11:00
PHST- 2000/07/06 11:00 [pubmed]
PHST- 2000/09/23 11:01 [medline]
PHST- 2000/07/06 11:00 [entrez]
AID - 10.1038/35017062 [doi]
PST - ppublish
SO  - Nat Cell Biol. 2000 Jul;2(7):428-34. doi: 10.1038/35017062.