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Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism

DOI: 10.1107/S205225252000696X DOI Help

Authors: Gustavo A. Bezerra (Structural Genomic Consortium, University of Oxford) , William R. Foster (Structural Genomics Consortium, University of Oxford) , Henry J. Bailey (Structural Genomics Consortium, University of Oxford) , Kevin G. Hicks (University of Utah School of Medicine) , Sven W. Sauer (University Hospital Heidelberg) , Bianca Dimitrov (University Hospital Heidelberg) , Thomas J. Mccorvie (Structural Genomics Consortium, University of Oxford) , Jürgen G. Okun (University Hospital Heidelberg) , Jared Rutter (University of Utah School of Medicine) , Stefan Kölker (University Hospital Heidelberg) , Wyatt W. Yue (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Iucrj , VOL 7

State: Published (Approved)
Published: July 2020

Open Access Open Access

Abstract: DHTKD1 is a lesser-studied E1 enzyme among the family of 2-oxoacid de­hydrogenases. In complex with E2 (di­hydro­lipo­amide succinyltransferase, DLST) and E3 (dihydrolipo­amide de­hydrogenase, DLD) components, DHTKD1 is involved in lysine and tryptophan catabolism by catalysing the oxidative de­carboxyl­ation of 2-oxoadipate (2OA) in mitochondria. Here, the 1.9 Å resolution crystal structure of human DHTKD1 is solved in complex with the thi­amine diphosphate co-factor. The structure reveals how the DHTKD1 active site is modelled upon the well characterized homologue 2-oxoglutarate (2OG) de­hydrogenase but engineered specifically to accommodate its preference for the longer substrate of 2OA over 2OG. A 4.7 Å resolution reconstruction of the human DLST catalytic core is also generated by single-particle electron microscopy, revealing a 24-mer cubic scaffold for assembling DHTKD1 and DLD protomers into a megacomplex. It is further demonstrated that missense DHTKD1 variants causing the inborn error of 2-amino­adipic and 2-oxoadipic aciduria impact on the complex formation, either directly by disrupting the interaction with DLST, or indirectly through destabilizing the DHTKD1 protein. This study provides the starting framework for developing DHTKD1 modulators to probe the intricate mitochondrial energy metabolism.

Journal Keywords: human DHTKD1; 2-oxoadipate; 2-oxoacid de­hydrogenase; thi­amine diphosphate; lysine catabolism; cryo-EM; enzyme mechanisms; multi-protein complexes

Subject Areas: Biology and Bio-materials

Instruments: B21-High Throughput SAXS , I03-Macromolecular Crystallography