| Literature DB >> 29499131 |
Silvia Escudero1, Elma Zaganjor2, Susan Lee1, Christopher P Mill3, Ann M Morgan1, Emily B Crawford1, Jiahao Chen4, Thomas E Wales5, Rida Mourtada1, James Luccarelli1, Gregory H Bird1, Ulrich Steidl4, John R Engen5, Marcia C Haigis2, Joseph T Opferman6, Loren D Walensky7.
Abstract
MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) α helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid β-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1Matrix) interacts with VLCAD. Mcl-1 deletion, or eliminating MCL-1Matrix alone, selectively deregulated long-chain FAO, causing increased flux through the pathway in response to nutrient deprivation. Transient elevation in MCL-1 upon serum withdrawal, a striking increase in MCL-1 BH3/VLCAD interaction upon palmitic acid titration, and direct modulation of enzymatic activity by the MCL-1 BH3 α helix are consistent with dynamic regulation. Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.Entities:
Keywords: BCL-2 family; MCL-1; VLCAD; apoptosis; fatty acid metabolism; mitochondria; mitochondrial matrix; stapled peptide; α helix; β-oxidation
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Year: 2018 PMID： 29499131 PMCID： PMC5916823 DOI： 10.1016/j.molcel.2018.02.005
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970