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

Darren Boehning | Zendy; Damian B. van Rossum | Zendy; Randen L. Patterson | Zendy; Solomon H. Snyder | Zendy

Open Access

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

Author(s) -

Darren Boehning,

Damian B. van Rossum,

Randen L. Patterson,

Solomon H. Snyder

Publication year - 2005

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.0409650102

Subject(s) - cytochrome c , inositol , microbiology and biotechnology , inositol trisphosphate receptor , staurosporine , jurkat cells , endoplasmic reticulum , inositol trisphosphate , biology , calcium signaling , apoptosis , receptor , programmed cell death , calcium , biochemistry , signal transduction , chemistry , protein kinase c , t cell , immunology , immune system , organic chemistry

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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