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Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening.

Publication ,  Journal Article
Nagai, Y; Tucker, T; Ren, H; Kenan, DJ; Henderson, BS; Keene, JD; Strittmatter, WJ; Burke, JR
Published in: J Biol Chem
April 7, 2000

Proteins with expanded polyglutamine domains cause eight inherited neurodegenerative diseases, including Huntington's, but the molecular mechanism(s) responsible for neuronal degeneration are not yet established. Expanded polyglutamine domain proteins possess properties that distinguish them from the same proteins with shorter glutamine repeats. Unlike proteins with short polyglutamine domains, proteins with expanded polyglutamine domains display unique protein interactions, form intracellular aggregates, and adopt a novel conformation that can be recognized by monoclonal antibodies. Any of these polyglutamine length-dependent properties could be responsible for the pathogenic effects of expanded polyglutamine proteins. To identify peptides that interfere with pathogenic polyglutamine interactions, we screened a combinatorial peptide library expressed on M13 phage pIII protein to identify peptides that preferentially bind pathologic-length polyglutamine domains. We identified six tryptophan-rich peptides that preferentially bind pathologic-length polyglutamine domain proteins. Polyglutamine-binding peptide 1 (QBP1) potently inhibits polyglutamine protein aggregation in an in vitro assay, while a scrambled sequence has no effect on aggregation. QBP1 and a tandem repeat of QBP1 also inhibit aggregation of polyglutamine-yellow fluorescent fusion protein in transfected COS-7 cells. Expression of QBP1 potently inhibits polyglutamine-induced cell death. Selective inhibition of pathologic interactions of expanded polyglutamine domains with themselves or other proteins may be a useful strategy for preventing disease onset or for slowing progression of the polyglutamine repeat diseases.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 7, 2000

Volume

275

Issue

14

Start / End Page

10437 / 10442

Location

United States

Related Subject Headings

  • Transfection
  • Thioredoxins
  • Recombinant Fusion Proteins
  • Proteins
  • Peptides
  • Peptide Library
  • Oligopeptides
  • Molecular Sequence Data
  • Luminescent Proteins
  • Green Fluorescent Proteins
 

Citation

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Nagai, Y., Tucker, T., Ren, H., Kenan, D. J., Henderson, B. S., Keene, J. D., … Burke, J. R. (2000). Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening. J Biol Chem, 275(14), 10437–10442. https://doi.org/10.1074/jbc.275.14.10437
Nagai, Y., T. Tucker, H. Ren, D. J. Kenan, B. S. Henderson, J. D. Keene, W. J. Strittmatter, and J. R. Burke. “Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening.J Biol Chem 275, no. 14 (April 7, 2000): 10437–42. https://doi.org/10.1074/jbc.275.14.10437.
Nagai Y, Tucker T, Ren H, Kenan DJ, Henderson BS, Keene JD, et al. Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening. J Biol Chem. 2000 Apr 7;275(14):10437–42.
Nagai, Y., et al. “Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening.J Biol Chem, vol. 275, no. 14, Apr. 2000, pp. 10437–42. Pubmed, doi:10.1074/jbc.275.14.10437.
Nagai Y, Tucker T, Ren H, Kenan DJ, Henderson BS, Keene JD, Strittmatter WJ, Burke JR. Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening. J Biol Chem. 2000 Apr 7;275(14):10437–10442.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 7, 2000

Volume

275

Issue

14

Start / End Page

10437 / 10442

Location

United States

Related Subject Headings

  • Transfection
  • Thioredoxins
  • Recombinant Fusion Proteins
  • Proteins
  • Peptides
  • Peptide Library
  • Oligopeptides
  • Molecular Sequence Data
  • Luminescent Proteins
  • Green Fluorescent Proteins