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Enzymatic generation of the amino terminus of the beta-amyloid peptide.

Publication ,  Journal Article
Sahasrabudhe, SR; Brown, AM; Hulmes, JD; Jacobsen, JS; Vitek, MP; Blume, AJ; Sonnenberg, JL
Published in: J Biol Chem
August 5, 1993

The major pathological change in Alzheimer's disease is the deposition of 39-42-amino acid beta-amyloid peptide (BAP) in the brain. Since BAP begins at the aspartate residue (Asp1, or codon 672 of the amyloid precursor protein (APP)770 transcript), the ability of several proteases to cleave the peptide bond methionine-Asp1 (M/D) was evaluated by using peptides and recombinant APP molecules as substrates. Cathepsin G and chymotrypsin cleave the synthetic peptide HSEVKMDAEF at M/D under acidic conditions, whereas cleavage at lysine-methionine (K/M) predominates when the pH is alkaline. Trypsin and cathepsins B, D, and L are unable to cleave the synthetic peptide at M/D. Peptide SEVNLDAEF, representing the mutation found in early onset Alzheimer's disease families from Sweden, is cleaved by cathepsin G and chymotrypsin at leucine-aspartate (L/D). Incubation of cathepsin G with soluble protease nexin-2 obtained from recombinant APP (APP-REP) derivatives resulted in proteolytic cleavage at or near the amino terminus of BAP. Cathepsin G-mediated cleavage was also observed in the domain representing the amino terminus of BAP when mature plasma membrane-associated APP-REP molecules were used as substrates. Our results strongly suggest the involvement of a chymotrypsin-like serine protease in the generation of the amino terminus of BAP beginning at Asp1.

Duke Scholars

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

August 5, 1993

Volume

268

Issue

22

Start / End Page

16699 / 16705

Location

United States

Related Subject Headings

  • Trypsin
  • Substrate Specificity
  • Serine Endopeptidases
  • Precipitin Tests
  • Peptide Fragments
  • Molecular Sequence Data
  • Humans
  • Chymotrypsin
  • Cathepsins
  • Cathepsin G
 

Citation

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Sahasrabudhe, S. R., Brown, A. M., Hulmes, J. D., Jacobsen, J. S., Vitek, M. P., Blume, A. J., & Sonnenberg, J. L. (1993). Enzymatic generation of the amino terminus of the beta-amyloid peptide. J Biol Chem, 268(22), 16699–16705.
Sahasrabudhe, S. R., A. M. Brown, J. D. Hulmes, J. S. Jacobsen, M. P. Vitek, A. J. Blume, and J. L. Sonnenberg. “Enzymatic generation of the amino terminus of the beta-amyloid peptide.J Biol Chem 268, no. 22 (August 5, 1993): 16699–705.
Sahasrabudhe SR, Brown AM, Hulmes JD, Jacobsen JS, Vitek MP, Blume AJ, et al. Enzymatic generation of the amino terminus of the beta-amyloid peptide. J Biol Chem. 1993 Aug 5;268(22):16699–705.
Sahasrabudhe, S. R., et al. “Enzymatic generation of the amino terminus of the beta-amyloid peptide.J Biol Chem, vol. 268, no. 22, Aug. 1993, pp. 16699–705.
Sahasrabudhe SR, Brown AM, Hulmes JD, Jacobsen JS, Vitek MP, Blume AJ, Sonnenberg JL. Enzymatic generation of the amino terminus of the beta-amyloid peptide. J Biol Chem. 1993 Aug 5;268(22):16699–16705.

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

August 5, 1993

Volume

268

Issue

22

Start / End Page

16699 / 16705

Location

United States

Related Subject Headings

  • Trypsin
  • Substrate Specificity
  • Serine Endopeptidases
  • Precipitin Tests
  • Peptide Fragments
  • Molecular Sequence Data
  • Humans
  • Chymotrypsin
  • Cathepsins
  • Cathepsin G