Structural Insight into Interactions between Dihydrolipoamide Dehydrogenase (E3) and E3 Binding Protein of Human Pyruvate Dehydrogenase Complex
- 1 March 2006
- journal article
- research article
- Published by Elsevier BV in Structure
- Vol. 14 (3), 611-621
- https://doi.org/10.1016/j.str.2006.01.001
Abstract
The 9.5 MDa human pyruvate dehydrogenase complex (PDC) utilizes the specific dihydrolipoamide dehydrogenase (E3) binding protein (E3BP) to tether the essential E3 component to the 60-meric core of the complex. Here, we report crystal structures of the binding domain (E3BD) of human E3BP alone and in complex with human E3 at 1.6 Å and 2.2 Å, respectively. The latter structure shows that residues from E3BD contact E3 across its 2-fold axis, resulting in one E3BD binding site on the E3 homodimer. Negligible conformational changes occur in E3BD upon its high-affinity binding to E3. Modifications of E3BD residues at the center of the E3BD/E3 interface impede E3 binding far more severely than those of residues on the periphery, validating the “hot spot” paradigm for protein interactions. A cluster of disease-causing E3 mutations located near the center of the E3BD/E3 interface prevents the efficient recruitment of these E3 variants by E3BP into the PDC, leading to the dysfunction of the PDC catalytic machine.Keywords
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