Molecular basis of HACD-TECR complex mediated very-long-chain fatty acid elongation reveal a potential target in colorectal cancer
Abstract
Very long-chain fatty acids (VLCFAs) are crucial for lipid homeostasis and physiological functions. The elongation of VLCFAs, which is mediated by four consecutive enzymes in the endoplasmic reticulum (ER), has been implicated in tumor progression. However, the molecular mechanisms underlying VLCFA elongation enzymes and their specific contributions to tumorigenesis remain largely elusive. Here, we demonstrate that trans-2-enoyl-CoA reductase (TECR) is upregulated in colorectal cancer (CRC). Structural and biochemical analyses revealed a conserved catalytic mechanism for TECR-mediated trans-2-enoyl-CoA reduction. Moreover, we show that TECR forms a stable complex with 3-hydroxyacyl-CoA dehydratase (HACD), to cooperatively drive VLCFA elongation. A unique U-shaped loop in HACD is critical for recognizing TECR. Disruption of the HACD–TECR interaction interface significantly suppresses CRC cell growth. Collectively, these findings elucidate the molecular mechanism of HACD–TECR-mediated VLCFA elongation and suggest a potential therapeutic strategy for CRC treatment by modulating VLCFA metabolism.
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