Dimerization interface of 3-hydroxyacyl-CoA dehydrogenase tunes the formation of its catalytic intermediate.
3-Hydroxyacyl-CoA dehydrogenase (HAD, EC 1.1.1.35) is a homodimeric enzyme localized in the mitochondrial matrix, which catalyzes the third step in fatty acid β-oxidation. The crystal structures of human HAD and subsequent complexes with cofactor/substrate enabled better understanding of HAD catalyt...
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doaj-0190683f15a04f72ae59a7d886f5c5032020-11-24T22:04:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0194e9596510.1371/journal.pone.0095965Dimerization interface of 3-hydroxyacyl-CoA dehydrogenase tunes the formation of its catalytic intermediate.Yingzhi XuHe LiYing-Hua JinJun FanFei Sun3-Hydroxyacyl-CoA dehydrogenase (HAD, EC 1.1.1.35) is a homodimeric enzyme localized in the mitochondrial matrix, which catalyzes the third step in fatty acid β-oxidation. The crystal structures of human HAD and subsequent complexes with cofactor/substrate enabled better understanding of HAD catalytic mechanism. However, numerous human diseases were found related to mutations at HAD dimerization interface that is away from the catalytic pocket. The role of HAD dimerization in its catalytic activity needs to be elucidated. Here, we solved the crystal structure of Caenorhabditis elegans HAD (cHAD) that is highly conserved to human HAD. Even though the cHAD mutants (R204A, Y209A and R204A/Y209A) with attenuated interactions on the dimerization interface still maintain a dimerization form, their enzymatic activities significantly decrease compared to that of the wild type. Such reduced activities are in consistency with the reduced ratios of the catalytic intermediate formation. Further molecular dynamics simulations results reveal that the alteration of the dimerization interface will increase the fluctuation of a distal region (a.a. 60-80) that plays an important role in the substrate binding. The increased fluctuation decreases the stability of the catalytic intermediate formation, and therefore the enzymatic activity is attenuated. Our study reveals the molecular mechanism about the essential role of the HAD dimerization interface in its catalytic activity via allosteric effects.http://europepmc.org/articles/PMC3999109?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yingzhi Xu He Li Ying-Hua Jin Jun Fan Fei Sun |
spellingShingle |
Yingzhi Xu He Li Ying-Hua Jin Jun Fan Fei Sun Dimerization interface of 3-hydroxyacyl-CoA dehydrogenase tunes the formation of its catalytic intermediate. PLoS ONE |
author_facet |
Yingzhi Xu He Li Ying-Hua Jin Jun Fan Fei Sun |
author_sort |
Yingzhi Xu |
title |
Dimerization interface of 3-hydroxyacyl-CoA dehydrogenase tunes the formation of its catalytic intermediate. |
title_short |
Dimerization interface of 3-hydroxyacyl-CoA dehydrogenase tunes the formation of its catalytic intermediate. |
title_full |
Dimerization interface of 3-hydroxyacyl-CoA dehydrogenase tunes the formation of its catalytic intermediate. |
title_fullStr |
Dimerization interface of 3-hydroxyacyl-CoA dehydrogenase tunes the formation of its catalytic intermediate. |
title_full_unstemmed |
Dimerization interface of 3-hydroxyacyl-CoA dehydrogenase tunes the formation of its catalytic intermediate. |
title_sort |
dimerization interface of 3-hydroxyacyl-coa dehydrogenase tunes the formation of its catalytic intermediate. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
3-Hydroxyacyl-CoA dehydrogenase (HAD, EC 1.1.1.35) is a homodimeric enzyme localized in the mitochondrial matrix, which catalyzes the third step in fatty acid β-oxidation. The crystal structures of human HAD and subsequent complexes with cofactor/substrate enabled better understanding of HAD catalytic mechanism. However, numerous human diseases were found related to mutations at HAD dimerization interface that is away from the catalytic pocket. The role of HAD dimerization in its catalytic activity needs to be elucidated. Here, we solved the crystal structure of Caenorhabditis elegans HAD (cHAD) that is highly conserved to human HAD. Even though the cHAD mutants (R204A, Y209A and R204A/Y209A) with attenuated interactions on the dimerization interface still maintain a dimerization form, their enzymatic activities significantly decrease compared to that of the wild type. Such reduced activities are in consistency with the reduced ratios of the catalytic intermediate formation. Further molecular dynamics simulations results reveal that the alteration of the dimerization interface will increase the fluctuation of a distal region (a.a. 60-80) that plays an important role in the substrate binding. The increased fluctuation decreases the stability of the catalytic intermediate formation, and therefore the enzymatic activity is attenuated. Our study reveals the molecular mechanism about the essential role of the HAD dimerization interface in its catalytic activity via allosteric effects. |
url |
http://europepmc.org/articles/PMC3999109?pdf=render |
work_keys_str_mv |
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