PMID- 8276862
OWN - NLM
STAT- MEDLINE
DCOM- 19940208
LR  - 20210210
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 269
IP  - 1
DP  - 1994 Jan 7
TI  - Secretion of beta-amyloid precursor protein involves multiple cleavage sites.
PG  - 627-32
AB  - A major histopathological feature of Alzheimer's disease is deposits of a 
      approximately 4-kDa beta-amyloid peptide derived by proteolytic processing from a 
      precursor, the beta-amyloid precursor protein (beta-APP). Proteolytic cleavage of 
      beta-APP within the approximately 4-kDa beta-amyloid domain permits the secretion 
      of the amino-terminal portion of beta-APP while concomitantly producing a 
      membrane bound approximately 9-kDa carboxyl-terminal fragment. We have 
      characterized the proteolytic cleavage site for beta-APP secretion by amino acid 
      sequence analysis of the approximately 9-kDa beta-APP carboxyl-terminal cleavage 
      product produced by recombinant and native expression systems. Recombinant 
      beta-APP was generated by a vaccinia virus expression system in CV-1 monkey 
      fibroblasts; endogenous beta-APP was obtained using a fibroblast line derived 
      from an individual with Down's syndrome. The sequences of both unlabeled and 
      metabolically radiolabeled approximately 9-kDa fragment from CV-1 cells reveal 
      that the major (60%) secretory cleavage site is after Lys16 of the beta-amyloid 
      domain as reported previously; however, an additional cleavage site is seen after 
      Phe19 (40%). Radiosequence analysis of the carboxyl-terminal fragment purified 
      from Down's syndrome fibroblasts indicates cleavage sites after Phe19, Glu22, and 
      Gly25 and not after Lys16. CV-1 cells expressing beta-APP mutants lacking 4 and 6 
      amino acids adjacent to Lys16 yielded approximately 9-kDa fragments with two 
      identical cleavage sites, neither of which occurred after the retained Lys16 but 
      were after Glu11 and His13. These data suggest that secretion of beta-APP 
      involves multiple proteinases and that the composition of these proteinases may 
      vary within different cell backgrounds.
FAU - Zhong, Z
AU  - Zhong Z
AD  - Scios Nova Inc., Mountain View, California 94043.
FAU - Higaki, J
AU  - Higaki J
FAU - Murakami, K
AU  - Murakami K
FAU - Wang, Y
AU  - Wang Y
FAU - Catalano, R
AU  - Catalano R
FAU - Quon, D
AU  - Quon D
FAU - Cordell, B
AU  - Cordell B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Oligodeoxyribonucleotides)
SB  - IM
MH  - Amino Acid Sequence
MH  - Amyloid beta-Protein Precursor/genetics/*metabolism
MH  - Animals
MH  - Base Sequence
MH  - Cells, Cultured
MH  - Down Syndrome/metabolism/pathology
MH  - Fibroblasts/metabolism
MH  - Haplorhini
MH  - Humans
MH  - Hydrolysis
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Oligodeoxyribonucleotides
MH  - Sequence Analysis/methods
MH  - Vaccinia virus/genetics
EDAT- 1994/01/07 00:00
MHDA- 1994/01/07 00:01
CRDT- 1994/01/07 00:00
PHST- 1994/01/07 00:00 [pubmed]
PHST- 1994/01/07 00:01 [medline]
PHST- 1994/01/07 00:00 [entrez]
AID - S0021-9258(17)42395-7 [pii]
PST - ppublish
SO  - J Biol Chem. 1994 Jan 7;269(1):627-32.