ORAI1
Domain
The Pro-rich region of ORAI1 (residues 3-47) functionally interacts with the polybasic Lys-rich region of STIM1 (residues 672-685) and regulates CRAC channel gating at negative membrane potentials.
Isoform alpha
AKAP5 association region (AKAR) mediates coupling of ORAI1 to AKAP5-dependent NFATC2/NFAT1 transcriptional responses.
Function
Pore-forming subunit of two major inward rectifying Ca(2+) channels at the plasma membrane: Ca(2+) release-activated Ca(2+) (CRAC) channels and arachidonate-regulated Ca(2+)-selective (ARC) channels (Probable) (PubMed:16645049, PubMed:16733527, PubMed:16807233, PubMed:16921383, PubMed:19249086, PubMed:19706554, PubMed:23307288, PubMed:26956484, PubMed:28219928). Assembles with ORAI2 and ORAI3 to form hexameric CRAC channels that mediate Ca(2+) influx upon depletion of endoplasmic reticulum Ca(2+) store and channel activation by Ca(2+) sensor STIM1, a process known as store-operated Ca(2+) entry (SOCE). Various pore subunit combinations may account for distinct CRAC channel spatiotemporal and cell-type specific dynamics. ORAI1 mainly contributes to the generation of Ca(2+) plateaus involved in sustained Ca(2+) entry and is dispensable for cytosolic Ca(2+) oscillations, whereas ORAI2 and ORAI3 generate oscillatory patterns. CRAC channels assemble in Ca(2+) signaling microdomains where Ca(2+) influx is coupled to calmodulin and calcineurin signaling and activation of NFAT transcription factors recruited to ORAI1 via AKAP5. Activates NFATC2/NFAT1 and NFATC3/NFAT4-mediated transcriptional responses. CRAC channels are the main pathway for Ca(2+) influx in T cells and promote the immune response to pathogens by activating NFAT-dependent cytokine and chemokine transcription (PubMed:16582901, PubMed:17442569, PubMed:19182790, PubMed:20354224, PubMed:22641696, PubMed:26221052, PubMed:32415068, PubMed:33941685). Assembles with ORAI3 to form channels that mediate store-independent Ca(2+) influx in response to inflammatory metabolites arachidonate or its derivative leukotriene C4, termed ARC and LRC channels respectively (PubMed:19622606, PubMed:32415068). Plays a prominent role in Ca(2+) influx at the basolateral membrane of mammary epithelial cells independently of the Ca(2+) content of endoplasmic reticulum or Golgi stores. May mediate transepithelial transport of large quantities of Ca(2+) for milk secretion (By similarity) (PubMed:20887894).
Isoform alpha
Pore-forming subunit of both CRAC and ARC channels. Couples Ca(2+) influx to NFAT-mediated transcriptional responses.
Isoform beta
Pore-forming subunit of CRAC channels exclusively.
Involvement in disease
Immunodeficiency 9
IMD9
An immune disorder characterized by recurrent infections, impaired activation and proliferative response of T-cells, decreased T-cell production of cytokines, and normal lymphocytes counts and serum immunoglobulin levels. In surviving patients ectodermal dysplasia with anhidrosis and non-progressive myopathy may be observed.
None
The disease is caused by variants affecting the gene represented in this entry.
Myopathy, tubular aggregate, 2
TAM2
A rare congenital myopathy characterized by regular arrays of membrane tubules on muscle biopsies without additional histopathological hallmarks. Tubular aggregates in muscle are structures of variable appearance consisting of an outer tubule containing either one or more microtubule-like structures or amorphous material. TAM2 patients have myopathy and pupillary abnormalities.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
N-glycosylated (PubMed:16921383, PubMed:19249086, PubMed:26956484). N-glycosylation inhibits channel activity in T cells (PubMed:26956484).
Ubiquitinated.
Cys-195 is oxidated, leading to inactivation of channel activity.
Sequence Similarities
Belongs to the Orai family.
Tissue Specificity
Expressed in naive CD4 and CD8 T cells (at protein level) (PubMed:26956484). Expressed at similar levels in naive and effector T helper cells (PubMed:20354224).
Cellular localization
- Cell membrane
- Multi-pass membrane protein
- Basolateral cell membrane
- Multi-pass membrane protein
- Upon store depletion, colocalizes with STIM1 in membrane punctae at ER-PM junctions (PubMed:19182790, PubMed:19249086, PubMed:26221052, PubMed:27185316).
- Isoform alpha
- Cell membrane
- Isoform beta
- Cell membrane
Alternative names
CRACM1, TMEM142A, ORAI1, Calcium release-activated calcium channel protein 1, Protein orai-1, Transmembrane protein 142A