Role of Calcium in Modulating the Conformational Landscape and Peptide Binding Induced Closing of Calmodulin.

J Phys Chem B

School of Chemical Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India.

Published: March 2021

AI Article Synopsis

  • Metal ions, particularly calcium, are crucial for various cellular functions and are sensed by proteins like calmodulin.
  • Calmodulin undergoes significant conformation changes upon calcium binding, which enhances its ability to interact with its target, smooth muscle myosin light chain kinase (smMLCK).
  • The study reveals that calcium influences calmodulin's flexibility and the specific domain that binds to smMLCK, leading to two suggested pathways for peptide binding based on calcium levels.

Article Abstract

Metal ions play an essential role in several cellular functions. Calcium is a ubiquitous regulator and is involved in numerous physiological processes. A class of proteins have evolved that sense calcium levels inside cells and act as effector molecules. Calmodulin is one such protein that gets activated after binding to calcium and thereafter interacts with its many targets. Calmodulin comprises two homologous domains that are connected by a flexible linker. The calcium-dependent flexibility of the linker results in numerous conformations of calmodulin. In this work using microsecond long MD simulations and well-tempered metadynamics, we explore how the calcium induced conformation dynamics of calmodulin is different from the inherent fluctuations of apocalmodulin and whether it has any role in preparing calmodulin for its interaction with its target-smooth muscle myosin light chain kinase (smMLCK). We have observed that calcium bound calmodulin could explore states that are predisposed toward peptide binding. We also found that though the binding of calmodulin to smMLCK peptide is calcium-independent, calcium regulates the domain to which the peptide will be bound. On the basis of our findings, we have proposed two alternate pathways for smMLCK peptide binding to calmodulin as directed by the ambient calcium concentrations. Our work proposes how calmodulin functions under physiologically dynamic calcium concentrations.

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Source
http://dx.doi.org/10.1021/acs.jpcb.1c00783DOI Listing

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