Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: mapping the site of binding.

Abstract

In brain and tumor cells, the hexokinase isoforms HK-I and HK-II bind to the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane. We have previously shown that HK-I decreases murine VDAC1 (mVDAC1) channel conductance, inhibits cytochrome c release, and protects against apoptotic cell death. Now, we define mVDAC1 residues, found in two cytoplasmic domains, involved in the interaction with HK-I. Protection against cell death by HK-I, as induced by overexpression of native or mutated mVDAC1, served to identify the mVDAC1 amino acids required for interaction with HK-I. HK-I binding to mVDAC1 either in isolated mitochondria or reconstituted in a bilayer was inhibited upon mutation of specific VDAC1 residues. HK-I anti-apoptotic activity was also diminished upon mutation of these amino acids. HK-I-mediated inhibition of cytochrome c release induced by staurosporine was also diminished in cells expressing VDAC1 mutants. Our results thus offer new insights into the mechanism by which HK-I promotes tumor cell survival via inhibition of cytochrome c release through HK-I binding to VDAC1. These results, moreover, point to VDAC1 as a key player in mitochondrially mediated apoptosis and implicate an HK-I-VDAC1 interaction in the regulation of apoptosis. Finally, these findings suggest that interference with the binding of HK-I to mitochondria by VDAC1-derived peptides may offer a novel strategy by which to potentiate the efficacy of conventional chemotherapeutic agents.

• Authors: Salah Abu-Hamad, Hilal Zaid, Adrian Israelson, Edna Nahon, Varda Shoshan-Barmatz
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 19 Pg. 13482-90 (May 09 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18308720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Cytochromes c
• Voltage-Dependent Anion Channel 1
• Hexokinase

Topics

• Amino Acid Sequence
• Animals
• Apoptosis (drug effects)
• Binding Sites
• Cell Line
• Conserved Sequence
• Cytochromes c (metabolism)
• Cytosol (metabolism)
• Gene Expression Regulation
• Hexokinase (antagonists & inhibitors, genetics, metabolism)
• Humans
• Mice
• Molecular Sequence Data
• Mutation (genetics)
• Protein Binding
• Protein Kinase Inhibitors (pharmacology)
• Sequence Alignment
• Voltage-Dependent Anion Channel 1 (chemistry, genetics, metabolism)