Calmodulin and STIM proteins: Two major calcium sensors in the cytoplasm and endoplasmic reticulum

Biochem Biophys Res Commun. 2015 Apr 24;460(1):5-21. doi: 10.1016/j.bbrc.2015.01.106.


The calcium (Ca(2+)) ion is a universal signalling messenger which plays vital physiological roles in all eukaryotes. To decode highly regulated intracellular Ca(2+) signals, cells have evolved a number of sensor proteins that are ideally adapted to respond to a specific range of Ca(2+) levels. Among many such proteins, calmodulin (CaM) is a multi-functional cytoplasmic Ca(2+) sensor with a remarkable ability to interact with and regulate a plethora of structurally diverse target proteins. CaM achieves this 'multi-talented' functionality through two EF-hand domains, each with an independent capacity to bind targets, and an adaptable flexible linker. By contrast, stromal interaction molecule-1 and -2 (STIMs) have evolved for a specific role in endoplasmic reticulum (ER) Ca(2+) sensing using EF-hand machinery analogous to CaM; however, whereas CaM structurally adjusts to dissimilar binding partners, STIMs use the EF-hand machinery to self-regulate the stability of the Ca(2+) sensing domain. The molecular mechanisms underlying the Ca(2+)-dependent signal transduction by CaM and STIMs have revealed a remarkable repertoire of actions and underscore the flexibility of nature in molecular evolution and adaption to discrete Ca(2+) levels. Recent genomic sequencing efforts have uncovered a number of disease-associated mutations in both CaM and STIM1. This article aims to highlight the most recent key structural and functional findings in the CaM and STIM fields, and discusses how these two Ca(2+) sensor proteins execute their biological functions.

Keywords: Atomic resolution structure; Calcium sensing; Calmodulin; Calmodulin target interactions; EF-hand; Stromal interaction molecules (STIM).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / metabolism*
  • Calcium / metabolism*
  • Calcium Signaling / physiology
  • Calmodulin / genetics
  • Calmodulin / metabolism*
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cytoplasm / metabolism*
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Biological
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Stromal Interaction Molecule 1
  • Stromal Interaction Molecule 2


  • Calmodulin
  • Cell Adhesion Molecules
  • Membrane Proteins
  • Neoplasm Proteins
  • STIM1 protein, human
  • STIM2 protein, human
  • Stromal Interaction Molecule 1
  • Stromal Interaction Molecule 2
  • Calcium