From Stores to Sinks: Structural Mechanisms of Cytosolic Calcium Regulation.

All eukaryotic cells have adapted the use of the calcium ion (Ca) as a universal signaling element through the evolution of a toolkit of Ca sensor, buffer and effector proteins. Among these toolkit components, integral and peripheral proteins decorate biomembranes and coordinate the movement of Ca between compartments, sense these concentration changes and elicit physiological signals. These changes in compartmentalized Ca levels are not mutually exclusive as signals propagate between compartments. For example, agonist induced surface receptor stimulation can lead to transient increases in cytosolic Ca sourced from endoplasmic reticulum (ER) stores; the decrease in ER luminal Ca can subsequently signal the opening surface channels which permit the movement of Ca from the extracellular space to the cytosol. Remarkably, the minuscule compartments of mitochondria can function as significant cytosolic Ca sinks by taking up Ca in a coordinated manner. In non-excitable cells, inositol 1,4,5 trisphosphate receptors (IPRs) on the ER respond to surface receptor stimulation; stromal interaction molecules (STIMs) sense the ER luminal Ca depletion and activate surface Orai1 channels; surface Orai1 channels selectively permit the movement of Ca from the extracellular space to the cytosol; uptake of Ca into the matrix through the mitochondrial Ca uniporter (MCU) further shapes the cytosolic Ca levels. Recent structural elucidations of these key Ca toolkit components have improved our understanding of how they function to orchestrate precise cytosolic Ca levels for specific physiological responses. This chapter reviews the atomic-resolution structures of IPR, STIM1, Orai1 and MCU elucidated by X-ray crystallography, electron microscopy and NMR and discusses the mechanisms underlying their biological functions in their respective compartments within the cell.