Circadian Clock Protein KaiC

From Proteopedia

Revision as of 07:47, 4 December 2012

Introduction

Interactions of KaiC with KaiA and KaiB

Biological Circadian Clocks are self-sustaining oscillators that function on a rhythmic cycle of or around 24 hours. They are found in almost all organisms, the simplest of which are cyanobacteria, which have been extensively studied in order to determine the mechanism of the fine-tuned biological process of circadian rhythmicity. In most eukaryotes, a region of the brain called the superchiasmic nuclei detects light and dark cycles, then relays the message to biological clock systems that maintain rhythmicity within the body. Conversely, cyanobacteria have a fairly modest system comprised of three proteins: KaiC, KaiA, and KaiB. The system is based around the central protein KaiC which exhibits ATP binding, inter-subunit organization, a scaffold region for Kai protein complex formation, a location where critical mutations are found, and an evolutionary link to other well-known proteins ^[1]. In order to devise an explanation for the mechanism of biological oscillators, we need to characterize the structure, function, and interactions among molecular components. To study these, most scientists start with analyzing cyanobacteria, since it is the smallest organism that expresses circadian clock properties.

KaiC - KaiA - KaiB System

The system by which the protein complex maintains a precise tme constabnt and temperature compensation is acheived by the cooperation of a three-protein network. In a nutshell, KaiC requires ATP to autophosphorylate while KaiA enhances this phosphorylation and KaiB antagonizes it. KaiC is the central clock protein, which has autokinase and autophosphorylase activity. Yet in the presence of ATP alone, KaiC cannot perform it's autophosphorylation function. It requires two other proteins, KaiA and KaiB, the genes of which are found in the same cluster on the chromosome ^[1]. Although KaiC phosphorylates itself, the presence of KaiA and KaiB are essential to rhythmicity. KaiA stimulates KaiC autophosphorylation, possibly by stabilizing the phosphorylated form of KaiC. On the other hand, KaiB antagonizes the process possibly by enhancing KaiC dephosphorylation or interfering with the binding of KaiA to KaiC. Even in the presence of high ATP, KaiB still prompts KaiC to dephosphorylate ^[2]. The mechanism is not well understood and is the focus of further study.

KaiC Homohexameric Complex

KaiA <-> KaiC Interaction Site

KaiA is a protein that stabilizes the phosphorylation status of KaiC. This enhancer is hypothesized to bind to the interface of the two donut-shaped KaiC subunits, CI and CII. This area, known as the "waist" of the molecule, expresses head-to-tail orientation between CI and CII which regulates the essential phosphorylation by interacting with distant areas on the surface of the hexamer. Two possible sites are shown to present complementarity between KaiC and KaiA. On KaiC, these regions are located at the waist of the molecule and at the CII pore, or "dome" of the molecule.

KaiB <-> KaiC Interaction Site

(show 3D image of KaiC site for KaiB binding and highlight key residues in interaction -weak? strong? ions in site? how does it stabilize dephosphorylation/destabilize phosphorylation/destabilize KaiA?)

Biological Importance

- Nearly all promoters in a cyanobacteria are under circadian control. [function is important to whole life cycle] (1) - Structure similarity with RecA and DnaB. RecA is a DNA recombinase and DnaB is a DNA helicase, so the observation that there is similarity between these molecules imply possible direct interactions with DNA.

References