Calcineurin

Abstract

The serine/threonine phosphatase calcineurin acts as a crucial connection between calcium signaling the phosphorylation states of numerous important substrates. These substrates include, but are not limited to, transcription factors, receptors and channels, proteins associated with mitochondria, and proteins associated with microtubules. Calcineurin is activated by increases in intracellular calcium concentrations, a process that requires the calcium sensing protein calmodulin binding to an intrinsically disordered regulatory domain in the phosphatase. Despite having been studied for around four decades, the activation of calcineurin is not fully understood. This review largely focuses on what is known about the activation process and highlights aspects that are currently not understood. Video abstract.

Keywords: Calcineurin; Calcium; Calmodulin; Channels; Intrinsically-disordered region; Microtubules; Mitochondria; Receptors; Transcription.

Fig. 1

a. Domain structures of the CaN A chains from the three human isoforms. The residue numbering for αCaN was taken from the crystal structure (PDBID 1AUI [55];). For the β and γ isoforms, the regions of greatest difference with the α isoform are highlighted. b. Crystal structure of human αCaN (PDBID 1AUI [55];). The A chain is colored blue and the B chain green. The orange and yellow spheres denote a Zn-Fe center in the active site in the catalytic domain and the grey spheres denote Ca²⁺ bound to the B chain. Residues within the A chain between and beyond which electron density is not detected are indicated. The green oval denotes the location of the PxIxIT substrate binding site and the blue oval the LxVP substrate binding site

Fig. 2

Disorder predictions for the human αCnA (top panel) and CnB1 (bottom panel) chains. Values above 0.5 denote predicted disorder. Major regions of predicted disordered are marked with red bars

Fig. 3

Proposed models for the (a) inactive, (b) partially active, and c. fully active states of CaN. The inactive state (a) occurs at basal calcium concentrations and is thought to have the regulatory domain folded onto the B chain binding helix and the N-terminal lobe of CnB1 unbound. The partially active state (b) occurs when calcium is bound to CnB1 but prior to CaM binding. In this state the N-terminal lobe of CnB1 binds to the B chain binding helix, releasing the regulatory domain into a disordered state. The fully active state (c) occurs when holo-CaM has bound to CaN causing the regulatory domain to fold and removing the autoinhbitory domain from the active site

Fig. 4

a. Sequence of the regulatory domain (regulatory domain) from the human αCaN A chain with the CaM binding region denoted by the green box. b. 2:2 stoichiometric structure of holo-CaM bound to the CaM binding region from αCaN (PDBID 2R28 [93, 94];). Holo-CaM is colored green, the CaM binding region blue, and the grey spheres are Ca²⁺. C. 1:1 stoichiometric structure of holo-CaM bound to the CaM binding region from αCaN (PDBID 4Q5U [89];)