A Systematic Review of Chromogranin a (CGA) and its Biomedical Applications, Unveiling its Structure-Related Functions

Abstract

Across the domains of life, the molecular clock allows organisms to anticipate and respond to time-dependent events. At the center of the clock resides the core circadian oscillator, a tunable molecular timekeeper that maintains rhythms while also activating output pathways. While much has been learned regarding the molecular machinations of clocks, there remains a dearth of structural knowledge describing the details of oscillator function. In the cyanobacterial system, a phosphorylationrdephsophorylation cycle in the AAAþ ATPase KaiC governs rhythms within the S. elongatus cell. While it has been demonstrated that different phosphoforms of KaiC are biochemically distinct, having differing affinities for the other Kai proteins and ATPase rates, crystallization studies have been unable to detect significant structural changes in KaiC as it progresses throughout its circadian cycle. Our work on the cyanobacterial oscillator resolves this discrepancy by utilizing the technique of cryo-electron microscopy (Cryo-EM), a powerful tool for structural characterization that does not require sample crystallization. We have observed new conformations of KaiC in phophomimetic mutants that recapitulate KaiC at different circadian timepoints. Our results show that KaiC undergoes large structural changes that are dependent upon its phosphorylation state.