Molecular insights on cytochrome c and nucleotide regulation of apoptosome function and its implication in cancer

Yadav, Neelu; Gogada, Raghu; O'Malley, Jordan; Gundampati, Ravi Kumar; Jayanthi, Srinivas; Hashmi, Sana; Lella, Ravi; Zhang, Dianmu; Wang, Jianmin; Kumar, Rahul; Suresh Kumar, Thallapuranam Krishnaswamy; Chandra, Dhyan

doi:10.1016/j.bbamcr.2019.118573

Title: Molecular insights on cytochrome c and nucleotide regulation of apoptosome function and its implication in cancer

Journal Article · Wed Jan 01 00:00:00 EST 2020 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

DOI:https://doi.org/10.1016/j.bbamcr.2019.118573· OSTI ID:1755277

Yadav, Neelu; Gogada, Raghu; O'Malley, Jordan; Gundampati, Ravi Kumar; Jayanthi, Srinivas; Hashmi, Sana; Lella, Ravi; Zhang, Dianmu; Wang, Jianmin; Kumar, Rahul; Suresh Kumar, Thallapuranam Krishnaswamy; Chandra, Dhyan

Cytochrome c (Cyt c) released from mitochondria interacts with Apaf-1 to form the heptameric apoptosome, which initiates the caspase cascade to execute apoptosis. Although lysine residue at 72 (K72) of Cyt c plays an important role in the Cyt c-Apaf-1 interaction, the underlying mechanism of interaction between Cyt c and Apaf-1 is still not clearly defined. Here we identified multiple lysine residues including K72, which are also known to interact with ATP, to play a key role in Cyt c-Apaf-1 interaction. Mutation of these lysine residues abrogates the apoptosome formation causing inhibition of caspase activation. Using in-silico molecular docking, we have identified Cyt c-binding interface on Apaf-1. Although mutant Cyt c shows higher affinity for Apaf-1, the presence of Cyt c-WT restores the apoptosome activity. ATP addition modulates only mutant Cyt c binding to Apaf-1 but not WT Cyt c binding to Apaf-1. Using TCGA and cBioPortal, we identified multiple mutations in both Apaf-1 and Cyt c that are predicted to interfere with apoptosome assembly. We also demonstrate that transcript levels of various enzymes involved with dATP or ATP synthesis are increased in various cancers. Silencing of nucleotide metabolizing enzymes such as ribonucleotide reductase subunit M1 (RRM1) and ATP-producing glycolytic enzymes PKM2 attenuated ATP production and enhanced caspase activation. These findings suggest important role for lysine residues of Cyt c and nucleotides in the regulation of apoptosome-dependent apoptotic cell death as well as demonstrate how these mutations and nucleotides may have a pivotal role in human diseases such as cancer.

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Research Organization:: Univ. of Arkansas, Fayetteville, AR (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: 02-01ER15161; FG02-01ER15161

OSTI ID:: 1755277

Alternate ID(s):: OSTI ID: 1577911; OSTI ID: 1804027

Journal Information:: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Name: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Vol. 1867 Journal Issue: 1; ISSN 0167-4889

Publisher:: ElsevierCopyright Statement

Country of Publication:: Netherlands

Language:: English

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Cited by: 17 works

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59 BASIC BIOLOGICAL SCIENCES
cytochrome c
apoptosome
caspase activation
tumorigenesis
mitochondria
nucleotides

Title: Molecular insights on cytochrome c and nucleotide regulation of apoptosome function and its implication in cancer

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