PMID- 10383380
OWN - NLM
STAT- MEDLINE
DCOM- 19990727
LR  - 20220309
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 27
DP  - 1999 Jul 2
TI  - Mutagenesis identifies new signals for beta-amyloid precursor protein
      endocytosis, turnover, and the generation of secreted fragments, including
      Abeta42.
PG  - 18851-6
AB  - It has long been assumed that the C-terminal motif, NPXY, is the internalization 
      signal for beta-amyloid precursor protein (APP) and that the NPXY tyrosine
      (Tyr743 by APP751 numbering, Tyr682 in APP695) is required for APP endocytosis.
      To evaluate this tenet and to identify the specific amino acids subserving APP
      endocytosis, we mutated all tyrosines in the APP cytoplasmic domain and amino
      acids within the sequence GYENPTY (amino acids 737-743). Stable cell lines
      expressing these mutations were assessed for APP endocytosis, secretion, and
      turnover. Normal APP endocytosis was observed for cells expressing Y709A, G737A, 
      and Y743A mutations. However, Y738A, N740A, and P741A or the double mutation of
      Y738A/P741A significantly impaired APP internalization to a level similar to that
      observed for cells lacking nearly the entire APP cytoplasmic domain (DeltaC),
      arguing that the dominant signal for APP endocytosis is the tetrapeptide YENP.
      Although not an APP internalization signal, Tyr743 regulates rapid APP turnover
      because half-life increased by 50% with the Y743A mutation alone. Secretion of
      the APP-derived proteolytic fragment, Abeta, was tightly correlated with APP
      internalization, such that Abeta secretion was unchanged for cells having normal 
      APP endocytosis but significantly decreased for endocytosis-deficient cell lines.
      Remarkably, secretion of the Abeta42 isoform was also reduced in parallel with
      endocytosis from internalization-deficient cell lines, suggesting an important
      role for APP endocytosis in the secretion of this highly pathogenic Abeta
      species.
FAU - Perez, R G
AU  - Perez RG
AD  - Departments of Psychiatry and Neurobiology & Anatomy, Allegheny University of the
      Health Sciences, Pittsburgh, Pennsylvania 15212, USA. perez@pitt.edu
FAU - Soriano, S
AU  - Soriano S
FAU - Hayes, J D
AU  - Hayes JD
FAU - Ostaszewski, B
AU  - Ostaszewski B
FAU - Xia, W
AU  - Xia W
FAU - Selkoe, D J
AU  - Selkoe DJ
FAU - Chen, X
AU  - Chen X
FAU - Stokin, G B
AU  - Stokin GB
FAU - Koo, E H
AU  - Koo EH
LA  - eng
GR  - R01 AG012376/AG/NIA NIH HHS/United States
GR  - AG06173/AG/NIA NIH HHS/United States
GR  - AG12376/AG/NIA NIH HHS/United States
GR  - NS01812/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  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Peptide Fragments)
RN  - 0 (amyloid beta-protein (1-42))
SB  - IM
MH  - Amino Acid Sequence
MH  - Amyloid beta-Peptides/*metabolism
MH  - Amyloid beta-Protein Precursor/chemistry/*genetics/metabolism
MH  - Animals
MH  - CHO Cells
MH  - Cricetinae
MH  - *Endocytosis
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Peptide Fragments/*metabolism
MH  - Structure-Activity Relationship
EDAT- 1999/06/26 00:00
MHDA- 1999/06/26 00:01
CRDT- 1999/06/26 00:00
PHST- 1999/06/26 00:00 [pubmed]
PHST- 1999/06/26 00:01 [medline]
PHST- 1999/06/26 00:00 [entrez]
AID - 10.1074/jbc.274.27.18851 [doi]
AID - S0021-9258(19)74092-7 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Jul 2;274(27):18851-6. doi: 10.1074/jbc.274.27.18851.