title: Robust and tunable circadian rhythms from differentially sensitive catalytic domains.
abstract: Circadian clocks are ubiquitous biological oscillators that coordinate an organism's behavior with the daily cycling of the external environment. To ensure synchronization with the environment, the period of the clock must be maintained near 24 h even as amplitude and phase are altered by input signaling. We show that, in a reconstituted circadian system from cyanobacteria, these conflicting requirements are satisfied by distinct functions for two domains of the central clock protein KaiC: the C-terminal autokinase domain integrates input signals through the ATP/ADP ratio, and the slow N-terminal ATPase acts as an input-independent timer. We find that phosphorylation in the C-terminal domain followed by an ATPase cycle in the N-terminal domain is required to form the inhibitory KaiB•KaiC complexes that drive the dynamics of the clock. We present a mathematical model in which this ATPase-mediated delay in negative feedback gives rise to a compensatory mechanism that allows a tunable phase and amplitude while ensuring a robust circadian period.
authors.affiliation: Department of Molecular Genetics and Cell Biology, Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Phong
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Markson
authors.forename: Crystal M
authors.initials: CM
authors.lastname: Wilhoite
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rust
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000458:Cyanobacteria / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D056925:Circadian Rhythm Signaling Peptides and Proteins; C114270:KaiB protein, cyanobacteria; C114271:KaiC protein, cyanobacteria; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases