Calcineurin
- PDF / 2,893,323 Bytes
- 12 Pages / 595.276 x 790.866 pts Page_size
- 57 Downloads / 168 Views
(2020) 18:137
REVIEW
Open Access
Calcineurin Trevor P. Creamer
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. Keywords: Calcineurin, Calmodulin, Calcium, Intrinsically-disordered region, Transcription, Receptors, Channels, Mitochondria, Microtubules
Background The serine/threonine phosphatase calcineurin (CaN) is activated by increased intracellular calcium concentrations [1–4]. Along with the calmodulin-activated kinases [5], CaN directly links calcium signaling to protein phosphorylation states and plays an essential role in numerous signaling processes [6]. CaN is found in eukaryotes and is conserved from single cell organisms through to Homo sapiens [2, 7]. Although this review deals primarily with the human isoforms, much of what is covered should be applicable to other organisms. This review will largely focus on how calcium acts to activate CaN but will start with a brief introduction to how CaN is coupled to calcium signaling, and to some of the phosphatase’s substrates and the signaling processes of which they are a part (summarized in Table 1). This should not be taken as an exhaustive list of substrates nor a definitive description of how CaN modulates their activities. Indeed, how CaN recognizes its substrates is an active area of study, and there are
Correspondence: [email protected] Center for Structural Biology, Department of Molecular & Cellular Biochemistry, 741 S. Limestone Street, Lexington, KY 40536-0509, USA
ongoing efforts to identify and characterize more CaN substrates [32, 33].
Signaling Calcium signaling, calcineurin, and calmodulin
CaN is activated in response to increases in calcium concentrations in the cell [1, 2, 34]. The molecular details of the activation process will be discussed in detail below, but in short both CaN and the calcium-sensing protein calmodulin (CaM) bind calcium, with CaM then binding to CaN. The CaM:CaN complex forms the active phosphatase. This process directly couples calcium signaling to dephosphorylation in much the same way that calcium signaling is coupled to phosphorylation through the CaM-modulated kinases [5]. One notable difference however is that there are multiple CaM-modulated kinases but CaN is the only phosphatase known to be directly activated by calcium. A brief discussion of CaM is warr
Data Loading...
