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A GH3-like domain in reaper is required for mitochondrial localization and induction of IAP degradation.

Publication ,  Journal Article
Olson, MR; Holley, CL; Gan, EC; Colón-Ramos, DA; Kaplan, B; Kornbluth, S
Published in: J Biol Chem
November 7, 2003

Reaper is a potent pro-apoptotic protein originally identified in a screen for Drosophila mutants defective in apoptotic induction. Multiple functions have been ascribed to this protein, including inhibition of IAPs (inhibitors of apoptosis); induction of IAP degradation; inhibition of protein translation; and when expressed in vertebrate cells, induction of mitochondrial cytochrome c release. Structure/function analysis of Reaper has identified an extreme N-terminal motif that appears to be sufficient for inhibition of IAP function. We report here that this domain, although required for IAP destabilization, is not sufficient. Moreover, we have identified a small region of Reaper, similar to the GH3 domain of Grim, that is required for localization of Reaper to mitochondria, induction of IAP degradation, and potent cell killing. Although a mutant Reaper protein lacking the GH3 domain was deficient in these properties, these defects could be fully rectified by appending either the C-terminal mitochondrial targeting sequence from Bcl-xL or a homologous region from the pro-apoptotic protein HID. Together, these data strongly suggest that IAP destabilization by Reaper in intact cells requires Reaper localization to mitochondria and that induction of IAP instability by Reaper is important for the potent induction of apoptosis in Drosophila cells.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 7, 2003

Volume

278

Issue

45

Start / End Page

44758 / 44768

Location

United States

Related Subject Headings

  • bcl-X Protein
  • Transfection
  • Structure-Activity Relationship
  • Saccharomyces cerevisiae
  • Red Fluorescent Protein
  • Recombinant Fusion Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Protein Structure, Secondary
  • Peptide Fragments
  • Neuropeptides
 

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Olson, M. R., Holley, C. L., Gan, E. C., Colón-Ramos, D. A., Kaplan, B., & Kornbluth, S. (2003). A GH3-like domain in reaper is required for mitochondrial localization and induction of IAP degradation. J Biol Chem, 278(45), 44758–44768. https://doi.org/10.1074/jbc.M308055200
Olson, Michael R., Christopher L. Holley, Eugene C. Gan, Daniel A. Colón-Ramos, Bruce Kaplan, and Sally Kornbluth. “A GH3-like domain in reaper is required for mitochondrial localization and induction of IAP degradation.J Biol Chem 278, no. 45 (November 7, 2003): 44758–68. https://doi.org/10.1074/jbc.M308055200.
Olson MR, Holley CL, Gan EC, Colón-Ramos DA, Kaplan B, Kornbluth S. A GH3-like domain in reaper is required for mitochondrial localization and induction of IAP degradation. J Biol Chem. 2003 Nov 7;278(45):44758–68.
Olson, Michael R., et al. “A GH3-like domain in reaper is required for mitochondrial localization and induction of IAP degradation.J Biol Chem, vol. 278, no. 45, Nov. 2003, pp. 44758–68. Pubmed, doi:10.1074/jbc.M308055200.
Olson MR, Holley CL, Gan EC, Colón-Ramos DA, Kaplan B, Kornbluth S. A GH3-like domain in reaper is required for mitochondrial localization and induction of IAP degradation. J Biol Chem. 2003 Nov 7;278(45):44758–44768.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 7, 2003

Volume

278

Issue

45

Start / End Page

44758 / 44768

Location

United States

Related Subject Headings

  • bcl-X Protein
  • Transfection
  • Structure-Activity Relationship
  • Saccharomyces cerevisiae
  • Red Fluorescent Protein
  • Recombinant Fusion Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Protein Structure, Secondary
  • Peptide Fragments
  • Neuropeptides