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Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism
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 decarb...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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International Union of Crystallography
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340257/ https://www.ncbi.nlm.nih.gov/pubmed/32695416 http://dx.doi.org/10.1107/S205225252000696X |
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author | Bezerra, Gustavo A. Foster, William R. Bailey, Henry J. Hicks, Kevin G. Sauer, Sven W. Dimitrov, Bianca McCorvie, Thomas J. Okun, Jürgen G. Rutter, Jared Kölker, Stefan Yue, Wyatt W. |
author_facet | Bezerra, Gustavo A. Foster, William R. Bailey, Henry J. Hicks, Kevin G. Sauer, Sven W. Dimitrov, Bianca McCorvie, Thomas J. Okun, Jürgen G. Rutter, Jared Kölker, Stefan Yue, Wyatt W. |
author_sort | Bezerra, Gustavo A. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7340257 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | International Union of Crystallography |
record_format | MEDLINE/PubMed |
spelling | pubmed-73402572020-07-20 Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism Bezerra, Gustavo A. Foster, William R. Bailey, Henry J. Hicks, Kevin G. Sauer, Sven W. Dimitrov, Bianca McCorvie, Thomas J. Okun, Jürgen G. Rutter, Jared Kölker, Stefan Yue, Wyatt W. IUCrJ Research Papers 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. International Union of Crystallography 2020-06-10 /pmc/articles/PMC7340257/ /pubmed/32695416 http://dx.doi.org/10.1107/S205225252000696X Text en © Bezerra et al. 2020 http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Research Papers Bezerra, Gustavo A. Foster, William R. Bailey, Henry J. Hicks, Kevin G. Sauer, Sven W. Dimitrov, Bianca McCorvie, Thomas J. Okun, Jürgen G. Rutter, Jared Kölker, Stefan Yue, Wyatt W. Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism |
title | Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism |
title_full | Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism |
title_fullStr | Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism |
title_full_unstemmed | Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism |
title_short | Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism |
title_sort | crystal structure and interaction studies of human dhtkd1 provide insight into a mitochondrial megacomplex in lysine catabolism |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340257/ https://www.ncbi.nlm.nih.gov/pubmed/32695416 http://dx.doi.org/10.1107/S205225252000696X |
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