Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism
| Autor: | Stefan Koelker, Gustavo Arruda Bezerra, Wyatt W. Yue, Bianca Dimitrov, W. Foster, Juergen G. Okun, Henry J. Bailey, Kevin G. Hicks, Sven W. Sauer, Jared Rutter |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences biology Chemistry 030302 biochemistry & molecular biology Lysine Dehydrogenase Mitochondrion Small molecule Cofactor 03 medical and health sciences Enzyme Biochemistry biology.protein DHTKD1 Oxidative decarboxylation 030304 developmental biology |
| DOI: | 10.1101/2020.01.20.912931 |
| Popis: | DHTKD1 is a lesser-studied E1 enzyme belonging to the family of 2-oxoacid dehydrogenases. DHTKD1, in complex with the E2 (dihydrolipoamide succinyltransferase, DLST) and E3 (lipoamide dehydrogenase, DLD) components, is implicated in lysine and tryptophan catabolism by catalysing the oxidative decarboxylation of 2-oxoadipate (2OA) in the mitochondria. Here, we solved the crystal structure of human DHTKD1 at 1.9 Å resolution in binary complex with the thiamine diphosphate (ThDP) cofactor. Our structure explains the evolutionary divergence of DHTKD1 from the well-characterized homologue 2-oxoglutarate (2OG) dehydrogenase, in its preference for the larger 2OA substrate than 2OG. InheritedDHTKD1missense mutations cause the lysine metabolic condition 2-aminoadipic and 2-oxoadipic aciduria. Reconstruction of the missense variant proteins reveal their underlying molecular defects, which include protein destabilisation, disruption of protein-protein interactions, and alterations in the protein surface. We further generated a 5.0 Å reconstruction of the human DLST inner core by single-particle electron microscopy, revealing a 24-mer cubic architecture that serves as a scaffold for assembly of DHTKD1 and DLD. This structural study provides a starting point to develop small molecule DHTKD1 inhibitors for probing mitochondrial energy metabolism. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|