A peptide inhibitor of cytochrome c/inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways.
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.
Boehning
Darren
D
Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
van Rossum
Damian B
DB
Patterson
Randen L
RL
Snyder
Solomon H
SH
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D016923:Cell Death / Q000187:drug effects*; D003001:Cloning, Molecular; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019169:Jurkat Cells; D007700:Kinetics; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010455:Peptides; D018160:Receptors, Cytoplasmic and Nuclear; D045304:Cytochromes c; D019311:Staurosporine