A three-level regulatory mechanism of the aldo-keto reductase subfamily AKR12D

Zhihong Xiao, Jinyin Zha, Xu Yang, Tingting Huang, Shuxin Huang, Qi Liu, Xiaozheng Wang, Jie Zhong, Jianting Zheng, Rubing Liang, Zixin Deng, Jian Zhang (), Shuangjun Lin () and Shaobo Dai ()
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Zhihong Xiao: Shanghai Jiao Tong University
Jinyin Zha: Shanghai Jiao Tong University School of Medicine
Xu Yang: Shanghai Jiao Tong University
Tingting Huang: Shanghai Jiao Tong University
Shuxin Huang: Shanghai Jiao Tong University
Qi Liu: Shanghai Jiao Tong University
Xiaozheng Wang: Shanghai Jiao Tong University
Jie Zhong: Shanghai Jiao Tong University School of Medicine
Jianting Zheng: Shanghai Jiao Tong University
Rubing Liang: Shanghai Jiao Tong University
Zixin Deng: Shanghai Jiao Tong University
Jian Zhang: Shanghai Jiao Tong University School of Medicine
Shuangjun Lin: Shanghai Jiao Tong University
Shaobo Dai: Shanghai Jiao Tong University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Modulation of protein function through allosteric regulation is central in biology, but biomacromolecular systems involving multiple subunits and ligands may exhibit complex regulatory mechanisms at different levels, which remain poorly understood. Here, we discover an aldo-keto reductase termed AKRtyl and present its three-level regulatory mechanism. Specifically, by combining steady-state and transient kinetics, X-ray crystallography and molecular dynamics simulation, we demonstrate that AKRtyl exhibits a positive synergy mediated by an unusual Monod-Wyman-Changeux (MWC) paradigm of allosteric regulation at low concentrations of the cofactor NADPH, but an inhibitory effect at high concentrations is observed. While the substrate tylosin binds at a remote allosteric site with positive cooperativity. We further reveal that these regulatory mechanisms are conserved in AKR12D subfamily, and that substrate cooperativity is common in AKRs across three kingdoms of life. This work provides an intriguing example for understanding complex allosteric regulatory networks.

Date: 2024
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DOI: 10.1038/s41467-024-46363-z

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