A peptide inhibitor of cytochrome c/inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways

Darren Boehning, Damian B. Van Rossum, Randen L. Patterson, Solomon H Snyder

Research output: Contribution to journalArticle

Abstract

Apoptotic stimuli augment intracellular calcium concentration through inositol 1,4,5-trisphosphate receptors (IP3R) on endoplasmic reticulum calcium stores. We previously discovered an apoptotic cascade wherein cytochrome c binds to IP3R early in apoptosis, resulting in dysregulated calcium release. Here we show that cytochrome c binding to IP 3R depends on a cluster of glutamic acid residues within the C terminus of the channel. A cell permeant peptide derived from this sequence displaces cytochrome c from IP3R and abrogates cell death induced by staurosporine treatment of HeLa cells and Fas ligand stimulation of Jurkat cells. Small-molecule inhibitors of cytochrome c/IP3R interactions may prove useful in treating disorders associated with inappropriate intrinsic and extrinsic apoptotic signaling.

Original languageEnglish (US)
Pages (from-to)1466-1471
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number5
DOIs
StatePublished - Feb 1 2005

Fingerprint

Cytochromes c1
Inositol
Cytochromes c
Cell Death
Peptides
Calcium
Inositol 1,4,5-Trisphosphate Receptors
Fas Ligand Protein
Jurkat Cells
Staurosporine
HeLa Cells
Endoplasmic Reticulum
Glutamic Acid
Apoptosis

Keywords

  • Apoptosis
  • Calcium
  • Caspase
  • Fas
  • T lymphoma

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

A peptide inhibitor of cytochrome c/inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways. / Boehning, Darren; Van Rossum, Damian B.; Patterson, Randen L.; Snyder, Solomon H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 5, 01.02.2005, p. 1466-1471.

Research output: Contribution to journalArticle

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