This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mammalian branched-chain alpha-ketoacid dehydrogenase (BCKD) complex is a member of the mitochondrial alpha-ketoacid dehydrogenase complexes including pyruvate dehydrogenase complex (PDC), alpha-ketoglutarate dehydrogenase complex (KGDC) and the BCKD complex, having similar structure and function. The mammalian BCKD consists of three catalytic components: a heterotetrameric (alpha2beta2) branched-chain alpha-ketoacid decarboxylase or E1, a homo-24 meric dihydrolipoyl transacylase or E2 and a homodimeric dihydrolipoamide dehydrogenase or E3. E1 and E2 components are specific for the BCKD complex, whereas the E3 component is common to all three alpha-ketoacid dehydrogenase complexes. In addition, the mammalian BCKD contains two regulatory enzymes: a specific kinase and a specific phosphatase that regulate activity of the BCKD through phosphorylation (inactivation) / dephosphorylation (activation) cycles. The BCKD is organized around the cubic E2 core, to which 12 copies of E1, and an unspecified number of copies of E3, the kinase and the phosphatase are attached through ionic interactions. The molecular mass of the BCKD multienzyme complex is estimated to be 4 x 106 daltons. The BCKD complex is deficient in patients inflicted by the inherited Maple Syrup Urine Disease (MSUD). This metabolic block results in the accumulation of toxic branched-chain alpha-ketoacids, manifested by often-fatal acidosis, neurological derangement and mental retardation. Structural insight into how human mutations disrupt the catalytic mechanism of the human BCKD complex will help develop strategies for ameliorating the MSUD phenotype.
Specific Aims : 1. To decipher the three-dimensional structure of the E2 core of the human BCKD complex by cryo-EM. 2. To discern the binding topology and molar ratios of E1 and E3 on the E2 scaffold.
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