Modulation of calmodulin lobes by different targets: an allosteric model with hemiconcerted conformational transitions

TL;DR

This paper presents an allosteric model based on the MWC framework to explain how calmodulin's lobes are modulated by different targets, affecting calcium affinity and conformational states, with implications for cellular signaling.

Contribution

It introduces a simple allosteric model that captures target-specific modulation of calmodulin's lobes and extends to multiple targets influencing calcium binding in vivo.

Findings

The model accurately describes calmodulin-lobe conformational changes.

Targets differentially modulate calcium affinity of calmodulin.

The approach can simulate complex target interactions in cellular environments.

Abstract

Calmodulin, the ubiquitous calcium-activated second messenger in eukaryotes, is an extremely versatile molecule involved in many biological processes: muscular contraction, synaptic plasticity, circadian rhythm, and cell cycle, among others. The protein is structurally organised into two globular lobes, joined by a flexible linker. Calcium modulates calmodulin activity by favoring a conformational transition of each lobe from a closed conformation to an open conformation. Most targets have a strong preference for one conformation over the other, and depending on the free calcium concentration in a cell, particular sets of targets will preferentially interact with calmodulin. In turn, targets can increase or decrease the calcium affinity of the calmodulin molecules to which they bind. Interestingly, experiments with the tryptic fragments showed that most targets have a much lower affinity for the N-lobe than for the C-lobe. Hence, the latter predominates in the formation of most calmodulin-target complexes. We showed that a relatively simple allosteric mechanism, based the classic MWC model, can capture the observed modulation of both the isolated C-lobe, and intact calmodulin, by individual targets. Moreover, our model can be naturally extended to study how the calcium affinity of a single pool of calmodulin is modulated by a mixture of competing targets in vivo.