A Peptide Inhibitor of Cytochrome C/inositol 1,4,5-trisphosphate Receptor Binding Blocks Intrinsic and Extrinsic Cell Death Pathways

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Jan 25

PMID 15665074

Citations 54

Authors

Darren Boehning

Damian B van Rossum

Randen L Patterson

Solomon H Snyder

Affiliations

Soon will be listed here.

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 IP3R 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.

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