M-LDH serves as a regulatory subunit of the cytosolic substrate-channelling complex in vivo

Sofija Jovanović, Aleksandar Jovanovic, Russell M Crawford

    Research output: Contribution to journalArticlepeer-review

    14 Citations (Scopus)

    Abstract

    Nucleoside diphosphate kinase A (NDPK-A) regulates the a1 isoform of the AMP-activated protein kinase (AMPK a1) selectively, independent of [AMP] and surrounding [ATP], by a process termed substrate channelling. Here, we show, using a range of empirically validated biochemical techniques, that the muscle form (M-LDH or LDH-A) and the heart form (H-LDH or LDH-B) of lactate dehydrogenase are physically associated with the liver cytosolic substrate-channelling complex such that M-LDH associates with NDPK-A, AMPKa1 and casein kinase 2 (CK2), whereas H-LDH associates with local NDPK-B. We find that the species of LDH bound to the substrate-channelling complex regulates the in vivo enzymatic activities of both AMPK and CK2, and has a downstream effect on the phospho-status of acetyl CoA carboxylase, a key regulator of cellular fat metabolism known to be a part of the cytosolic substrate-channelling complex in vivo. We hypothesise that the regulatory presence of LDH in the complex couples the substrate-channelling mechanism to both the glycolytic and redox states of the cell, allowing for efficient sensing of cell metabolic status, interfacing with the substrate-channelling complex and regulating the enzymatic activities of AMPK and CK2, two critical protein kinases.

    Original languageEnglish
    Pages (from-to)349-61
    Number of pages13
    JournalJournal of Molecular Biology
    Volume371
    Issue number2
    DOIs
    Publication statusPublished - 10 Aug 2007

    Keywords

    • Animals
    • Cytosol
    • Isoelectric Focusing
    • L-Lactate Dehydrogenase
    • Mice
    • Myocardium
    • Protein Binding
    • Protein Isoforms
    • Protein Subunits
    • RNA, Small Interfering
    • Rats
    • Recombinant Proteins
    • Substrate Specificity

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