Orai channels: key players in Ca2+ homeostasis

Abstract

Maintaining a precise calcium (Ca²⁺) balance is vital for cellular survival. The most prominent pathway to shuttle Ca²⁺ into cells is the Ca²⁺ release activated Ca²⁺ (CRAC) channel. Orai proteins are indispensable players in this central mechanism of Ca²⁺ entry. This short review traces the latest articles published in the field of CRAC channel signalling with a focus on the structure of the pore-forming Orai proteins, the propagation of the binding signal from STIM1 through the channel to the central pore and their role in human health and disease.

Figure 1. Schematic and structural representation of important domains in Orai1 proteins.

(a) Schematic representation of one hOrai1 monomer with important amino acids and regions highlighted. N-termini and C-termini are located inside the cytosol and range from aa1–91 and aa259–301, respectively. The ETON region (aa73–90) is highlighted in orange. The four TM-domains (TM1: aa92–106; TM2: aa118–140; TM3: aa174–197 and TM4: aa236–258) are connected via two extracellular loops (loop1 and loop3) and one intracellular loop (loop2). Important hOrai1 residues and domains highlighted in yellow represent unpolar, green basic, blue acidic and red neutral/ polar side chains. (b) Cross section through a 3D model of a hexameric hOrai1 channel, displaying two hOrai1 monomers facing each other with TM2-TM4 stabilizing the pore-forming TM1-helices. Important amino acid residues are highlighted as in (a). Additionally, side chains of amino acid residues facing the ion-conducting pore (left) and side chains of residues within TM2 and TM3 (right) crucial for stability of TM domains are depicted. (PDB number: 4HKR with adapted hOrai1 sequence described in Frischauf et al. [39]).