Regulation mechanism study of residues E318/319 for KaiC protein phosphorylation.

Authors

Wenxin Guo, Yuqing Zhao, Xing Ke, He Feng, Anbang Li, Yumeng Yan, Yunjie Zhao

Published in

Biophysical journal. Jun 22, 2026. Epub Jun 22, 2026.

Abstract

The biological clock is widely present in living organisms and regulates nearly all life processes. Cyanobacteria are known prokaryotes with the simplest biological clock for circadian rhythm. The KaiC hexamer serves as the core of the cyanobacterial clock and undergoes diurnal rhythm oscillations through phosphorylation and dephosphorylation to keep time. However, the precise role of individual residues during the phosphorylation process of KaiC remains unclear. Current experiments indicate that mutations at residues 318 and 319 completely inhibit the phosphorylation of KaiC protein. However, the molecular mechanism by which these mutations disturb the protein's internal structure and subsequently shut down the phosphorylation reaction remains an unsolved mystery. Here, we conducted molecular dynamics simulations and found that the mutations reduced the stability of the protein (especially the CII domain), making the phosphorylation sites more accessible to solvent, weakening the rigidity of residues near the ATP-binding pocket, and disrupting the coordination network of Mg²⁺. Additionally, we discovered that efficient phosphorylation of KaiC requires the catalytic function of E318 and the mediation of Mg²⁺ coordination by E319, both of which are indispensable. This study clarified the functions of residues 318 and 319 in the regulation of KaiC phosphorylation, strengthened the understanding of the molecular mechanism of the circadian rhythm clock cycle in cyanobacteria, and is expected to provide new intervention ideas for diseases related to circadian rhythm disorders, such as sleep disorders and metabolic syndrome.

PMID:
42324775
Bibliographic data and abstract were imported from PubMed on 22 Jun 2026.

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