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Structure of rat BCKD kinase: nucleotide-induced domain communication in a mitochondrial protein kinase.

ABSTRACT: Mitochondrial protein kinases (mPKs) are molecular switches that down-regulate the oxidation of branched-chain alpha-ketoacids and pyruvate. Elevated levels of these metabolites are implicated in disease states such as insulin-resistant Type II diabetes, branched-chain ketoaciduria, and primary lactic acidosis. We report a three-dimensional structure of a member of the mPK family, rat branched-chain alpha-ketoacid dehydrogenase kinase (BCK). BCK features a characteristic nucleotide-binding domain and a four-helix bundle domain. These two domains are reminiscent of modules found in protein histidine kinases (PHKs), which are involved in two-component signal transduction systems. Unlike PHKs, BCK dimerizes through direct interaction of two opposing nucleotide-binding domains. Nucleotide binding to BCK is uniquely mediated by both potassium and magnesium. Binding of ATP induces disorder-order transitions in a loop region at the nucleotide-binding site. These structural changes lead to the formation of a quadruple aromatic stack in the interface between the nucleotide-binding domain and the four-helix bundle domain, where they induce a movement of the top portion of two helices. Phosphotransfer induces further ordering of the loop region, effectively trapping the reaction product ADP, which explains product inhibition in mPKs. The BCK structure is a prototype for all mPKs and will provide a framework for structure-assisted inhibitor design for this family of kinases.

SUBMITTER: Machius M

PROVIDER: S-EPMC58710 | biostudies-literature | 2001 Sep

REPOSITORIES: biostudies-literature

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Structure of rat BCKD kinase: nucleotide-induced domain communication in a mitochondrial protein kinase.

Machius M M Chuang J L JL Wynn R M RM Tomchick D R DR Chuang D T DT

Proceedings of the National Academy of Sciences of the United States of America 20010918 20

Mitochondrial protein kinases (mPKs) are molecular switches that down-regulate the oxidation of branched-chain alpha-ketoacids and pyruvate. Elevated levels of these metabolites are implicated in disease states such as insulin-resistant Type II diabetes, branched-chain ketoaciduria, and primary lactic acidosis. We report a three-dimensional structure of a member of the mPK family, rat branched-chain alpha-ketoacid dehydrogenase kinase (BCK). BCK features a characteristic nucleotide-binding domai ...[more]

PMID: 11562470

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Project description:Perfluorinated alkyl acids (PFAAs) represent a broad class of commercial products designed primarily for the coatings industry. However, detection of residues globally in a variety of species led to the discontinuation of production in the U.S. Although PFAAs cause activation of the PPAR? and CAR nuclear receptors, interference with mitochondrial bioenergetics has been implicated as an alternative mechanism of cytotoxicity. Although the mechanisms by which the eight carbon chain PFAAs interfere with mitochondrial bioenergetics are fairly well described, the activities of the more highly substituted or shorter chain PFAAs are far less well characterized. The current investigation was designed to explore structure-activity relationships by which PFAAs interfere with mitochondrial respiration in vitro. Freshly isolated rat liver mitochondria were incubated with one of 16 different PFAAs, including perfluorinated carboxylic, acetic, and sulfonic acids, sulfonamides and sulfamido acetates, and alcohols. The effect on mitochondrial respiration was measured at five concentrations and dose-response curves were generated to describe the effects on state 3 and 4 respiration and respiratory control. With the exception of PFOS, all PFAAs at sufficiently high concentrations (>20?M) stimulated state 4 and inhibited state 3 respiration. Stimulation of state 4 respiration was most pronounced for the carboxylic acids and the sulfonamides, which supports prior evidence that the perfluorinated carboxylic and acetic acids induce the mitochondrial permeability transition, whereas the sulfonamides are protonophoric uncouplers of oxidative phosphorylation. In both cases, potency increased with increasing carbon number, with a prominent inflection point between the six and eight carbon congeners. The results provide a foundation for classifying PFAAs according to specific modes of mitochondrial activity and, in combination with toxicokinetic considerations, establishing structure-activity-based boundaries for initial estimates of risk for noncancer endpoints for PFAAs for which minimal in vivo toxicity testing currently exists.

Dataset Information

Structure of rat BCKD kinase: nucleotide-induced domain communication in a mitochondrial protein kinase.

Publications

Structure of rat BCKD kinase: nucleotide-induced domain communication in a mitochondrial protein kinase.

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