ORAI1 Membrane Protein Introduction

Introduction of ORAI1

Calcium release-activated calcium channel protein 1 (CRACM1), also known as IMD9, TAM2, ORAT1, ORAI1 or TMEM142A, is a calcium selective ion channel that in humans is encoded by the ORAI1 gene. ORAI1 is a pore subunit of Ca²⁺ release-activated Ca²⁺ (CRAC) channel with four putative transmembrane segments (TMs) arranged in concentric layers, with the centrally located TM1 helices lining the pore, TM2 and TM3 in the next layer, and TM4 forming the most external, lipid-exposed segment. The cytoplasmic C terminus of ORAI1 is required for its interaction with STIM1 (an essential component for the activation of CRAC channel).

Basic Information of ORAI1
Protein Name	Calcium release-activated calcium channel protein 1
Gene Name	ORAI1
Aliases	Protein orai-1, Transmembrane protein 142A
Organism	Homo sapiens (Human)
UniProt ID	Q96D31
Transmembrane Times	4
Length (aa)	301
Sequence	MHPEPAPPPSRSSPELPPSGGSTTSGSRRSRRRSGDGEPPGAPPPPPSAVTYPDWIGQSYSEVMSLNEHSMQALSWRKLYLSRAKLKASSRTSALLSGFAMVAMVEVQLDADHDYPPGLLIAFSACTTVLVAVHLFALMISTCILPNIEAVSNVHNLNSVKESPHERMHRHIELAWAFSTVIGTLLFLAEVVLLCWVKFLPLKKQPGQPRPTSKPPASGAAANVSTSGITPGQAAAIASTTIMVPFGLIFIVFAVHFYRSLVSHKTDRQFQELNELAEFARLQDQLDHRGDHPLTPGSHYA

Function of ORAI1 Membrane Protein

As an essential component or regulator of the CRAC channel, the main role of ORAI1 is to mediate Ca²⁺ influx through the plasma membrane to maintain the balance of cellular calcium. Notably, in order to mediate exceedingly selective Ca²⁺ entry, ORAI1 needs to migrate and become tethered by STIM within the ER-PM junctions. In addition, ORAI1 colocalized with T cell receptor molecules at the interface between T cells and dendritic cells, playing an important role in the activation of T-lymphocytes. Therefore, ORAI1 deficiency will lead to severe combined immunodeficiency (SCID) in humans. The function of ORAI1 is essential for T cell homing to lymph nodes. Additionally, there are many other biological processes associating with ORAI1, including mammary gland epithelium development, lymphocyte activation to defense infections, etc.

ORAI1 Membrane Protein Introduction Fig.1 Predicted structure of ORAI1 in ModBase. (Pieper, 2014)

Application of ORAI1 Membrane Protein in Literature

Sogkas G., et al. Orai1 controls C5a-induced neutrophil recruitment in inflammation. Eur J Immunol. 2015, 45(7): 2143-53. PubMed ID: 25912155

This article demonstrates that ORAI1 acts as an important signal regulator of activation of C5aR, involved in inflammation through a STIM1-independent pathway of Ca(2+)-influx in neutrophils.
Lacruz R.S. and Feske S. Diseases caused by mutations in ORAI1 and STIM1. Ann N Y Acad Sci. 2015, 1356: 45-79. PubMed ID: 26469693

This article demonstrates that loss-of-function mutations in ORAI1 and STIM1 that abolish CRAC channel function and store-operated Ca(2+) entry can lead to CRAC channelopathy; it is characterized by severe combined immunodeficiency (SCID)-like disease, muscular hypotonia, ectodermal dysplasia, and autoimmunity, with defects in dental enamel formation and sweat gland function.
Perni S., et al. Nanoscale patterning of STIM1 and Orai1 during store-operated Ca²⁺ entry. Proc Natl Acad Sci U S A. 2015, 112(40): E5533-42. PubMed ID: 26351694

This article offers direct, dramatic views of Orai1 clustering and STIM1 aggregation in store-depleted cells and provides direct evidence for the interaction of small clusters of STIM1 molecules with a single Orai1 channel.
Zhou Y., et al. STIM1 dimers undergo unimolecular coupling to activate Orai1 channels. Nat Commun. 2015, 6: 8395. PubMed ID: 26399906

This article predicts that STIM1 dimers may be associated with crosslinking between localization of Orai1 channel opening and Orai1 channels with implications for the kinetics.
Tirado-Lee L., et al. Conformational Changes in the Orai1 C-Terminus Evoked by STIM1 Binding. PLoS One. 2015, 10(6): e0128622. PubMed ID: 26035642

This article suggests that the modest rearrangement of self-associated Orai1 C-termini aims to accommodate STIM1 binding.

ORAI1 Preparation Options

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Reference

Pieper U, et al. (2016). ModBase, a database of annotated comparative protein structure models and associated resources. Nucleic Acids Res. 42: D336-46.

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