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Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1.

Site-specific proteolysis of the amyloid-beta precursor protein (APP) by BACE 1 and gamma-secretase, a central event in Alzheimer disease, releases a large secreted extracellular fragment (called APP(S)), peptides of 40-43 residues derived from extracellular and transmembrane sequences (Abeta), and a short intracellular fragment (APP intracellular domain) that may function as a transcriptional activator in a complex with the adaptor protein Fe65 and the nuclear protein Tip60. APP is closely related to APP-like protein (APLP) 1 and APLP2, but only APP is known to be cleaved by BACE 1 and to be involved in Alzheimer disease. We now demonstrate that similar to APP, APLP1 and APLP2 are also cleaved by BACE 1 but not by ADAM 9, another APP protease, and also transactivate nuclear Tip60 in a complex with Fe65. Paradoxically, although BACE 1 cleavage appears to be specific for APP and APLPs, their cleavage sequences exhibit no homology, and a short sequence (7 amino acids) from APP that when placed close to the membrane converts a membrane protein that is normally not cleaved by BACE 1 into a BACE 1 substrate. Our data demonstrate that APLPs and APP are processed similarly to act via the same nuclear target, suggesting that BACE 1 cleavage regulates a common function of APP and APLPs in neurons.

Pubmed ID: 14699153


  • Li Q
  • S├╝dhof TC


The Journal of biological chemistry

Publication Data

March 12, 2004

Associated Grants

  • Agency: NIMH NIH HHS, Id: R01-MH69585-01

Mesh Terms

  • ADAM Proteins
  • Acetyltransferases
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor
  • Animals
  • Aspartic Acid Endopeptidases
  • COS Cells
  • Cell Line
  • Cell Nucleus
  • Disintegrins
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Endopeptidases
  • Genetic Vectors
  • HeLa Cells
  • Histone Acetyltransferases
  • Humans
  • Immunoblotting
  • Membrane Proteins
  • Metalloendopeptidases
  • Models, Genetic
  • Molecular Sequence Data
  • Nerve Tissue Proteins
  • Neurons
  • Nuclear Proteins
  • Plasmids
  • Protein Binding
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection