PMID- 10097139
OWN - NLM
STAT- MEDLINE
DCOM- 19990512
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 7
DP  - 1999 Mar 30
TI  - Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid
      precursor protein by a disintegrin metalloprotease.
PG  - 3922-7
AB  - Amyloid beta peptide (Abeta), the principal proteinaceous component of amyloid
      plaques in brains of Alzheimer's disease patients, is derived by proteolytic
      cleavage of the amyloid precursor protein (APP). Proteolytic cleavage of APP by a
      putative alpha-secretase within the Abeta sequence precludes the formation of the
      amyloidogenic peptides and leads to the release of soluble APPsalpha into the
      medium. By overexpression of a disintegrin and metalloprotease (ADAM), classified
      as ADAM 10, in HEK 293 cells, basal and protein kinase C-stimulated
      alpha-secretase activity was increased severalfold. The proteolytically activated
      form of ADAM 10 was localized by cell surface biotinylation in the plasma
      membrane, but the majority of the proenzyme was found in the Golgi. These results
      support the view that APP is cleaved both at the cell surface and along the
      secretory pathway. Endogenous alpha-secretase activity was inhibited by a
      dominant negative form of ADAM 10 with a point mutation in the zinc binding site.
      Studies with purified ADAM 10 and Abeta fragments confirm the correct
      alpha-secretase cleavage site and demonstrate a dependence on the substrate's
      conformation. Our results provide evidence that ADAM 10 has alpha-secretase
      activity and many properties expected for the proteolytic processing of APP.
      Increases of its expression and activity might be beneficial for the treatment of
      Alzheimer's disease.
FAU - Lammich, S
AU  - Lammich S
AD  - Institut fur Biochemie, Johannes Gutenberg-Universitat, Mainz, Becherweg 30,
      D-55128 Mainz, Germany.
FAU - Kojro, E
AU  - Kojro E
FAU - Postina, R
AU  - Postina R
FAU - Gilbert, S
AU  - Gilbert S
FAU - Pfeiffer, R
AU  - Pfeiffer R
FAU - Jasionowski, M
AU  - Jasionowski M
FAU - Haass, C
AU  - Haass C
FAU - Fahrenholz, F
AU  - Fahrenholz F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (APPsalpha protein, mouse)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Membrane Proteins)
RN  - 0 (Peptide Fragments)
RN  - 0 (Recombinant Proteins)
RN  - EC 2.7.11.13 (Protein Kinase C)
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)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.81 (ADAM 10 protein, Bos taurus)
RN  - EC 3.4.24.81 (ADAM10 Protein)
RN  - EC 3.4.24.81 (ADAM10 protein, human)
RN  - J41CSQ7QDS (Zinc)
SB  - IM
MH  - ADAM Proteins
MH  - ADAM10 Protein
MH  - Amino Acid Sequence
MH  - Amyloid Precursor Protein Secretases
MH  - Amyloid beta-Protein Precursor/chemistry/*metabolism
MH  - Animals
MH  - Aspartic Acid Endopeptidases
MH  - Binding Sites
MH  - Cattle
MH  - Cell Line
MH  - Cloning, Molecular
MH  - Endopeptidases/*metabolism
MH  - Humans
MH  - Kidney/enzymology
MH  - Kinetics
MH  - Membrane Proteins/*genetics
MH  - Metalloendopeptidases/*genetics
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Peptide Fragments/chemistry/*metabolism
MH  - Point Mutation
MH  - Protein Kinase C/metabolism
MH  - Recombinant Proteins/metabolism
MH  - Substrate Specificity
MH  - Transfection
MH  - Zinc/metabolism
PMC - PMC22396
EDAT- 1999/03/31 00:00
MHDA- 1999/03/31 00:01
CRDT- 1999/03/31 00:00
PHST- 1999/03/31 00:00 [pubmed]
PHST- 1999/03/31 00:01 [medline]
PHST- 1999/03/31 00:00 [entrez]
AID - 10.1073/pnas.96.7.3922 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3922-7. doi: 10.1073/pnas.96.7.3922.