Disease relevance of TMEM142A

• The SCID patients are homozygous for a single missense mutation in ORAI1, and expression of wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (I(CRAC)) [1].

High impact information on TMEM142A

• Two proteins, STIM1 (the ER Ca(2+) sensor) and Orai1 (the Ca(2+) channel), have recently been identified as the missing links in SOCE [2].
• All three proteins were co-localized in the plasma membrane region of cells, and thapsigargin increased co-immunoprecipitation of TRPC1 with STIM1, and Orai1 in human salivary gland cells as well as dispersed mouse submandibular gland cells [3].
• This results in rearrangement of Stim1 within the cell and migration toward the plasma membrane to regulate in some manner Orai1 located in the plasma membrane [4].
• However, we demonstrate that Stim1 does not incorporate in the surface membrane, and thus likely regulates or interacts with Orai1 at sites of close apposition between the plasma membrane and an intracellular Stim1-containing organelle [4].
• Essential role of the N-terminus of murine Orai1 in store-operated Ca(2+) entry [5].

Biological context of TMEM142A

• By site-directed mutagenesis, we show that a point mutation from glutamate to aspartate at position 180 in the conserved S1-S2 loop of Orai transforms the ion selectivity properties of CRAC current from being Ca2+-selective with inward rectification to being selective for monovalent cations and outwardly rectifying [6].
• Recent RNA interference screens have identified several proteins that are essential for store-operated Ca2+ influx and Ca2+ release-activated Ca2+ (CRAC) channel activity in Drosophila and in mammals, including the transmembrane proteins Stim (stromal interaction molecule) and Orai [6].

Anatomical context of TMEM142A

• Here we show that Orai1 is a plasma membrane protein, and that CRAC channel function is sensitive to mutation of two conserved acidic residues in the transmembrane segments [7].

Associations of TMEM142A with chemical compounds

• Among the genes identified, Orai1 contains a distinctive proline- and arginine-rich N-terminal cytoplasmic sequence [5].
• STIM1, the putative calcium sensor in the endoplasmic reticulum, and the calcium release-activated calcium (CRAC) modulator CRACM1 (also known as Orai1) in the plasma membrane have recently been shown to be essential for controlling the store-operated CRAC current (I(CRAC)) [8].

Physical interactions of TMEM142A

• Direct Ca(2+) entry into the store is regulated by its filling status in a negative and positive manner through a Ca(2+)-binding protein and Stim1/Orai complex, respectively [9].

Co-localisations of TMEM142A

• We further demonstrate that Orai1 assembles into clusters that co-localize with STIM1 aggregations upon store depletion [10].

Regulatory relationships of TMEM142A

• Aggregation of STIM1 underneath the plasma membrane induces clustering of Orai1 [10].
• Single-channel cation currents present in membrane patches of TRPC3-overexpressing cells were suppressed by expression of Orai1 [11].
• The 55-amino-acid STIM2 terminus substituted within STIM1 strikingly enhances both Orai1-mediated Ca(2+) entry and constitutive coupling to activate Orai1 channels [12].

Other interactions of TMEM142A

• However, these experiments did not establish whether Orai is an essential intracellular link between STIM and the CRAC channel, an accessory protein in the plasma membrane, or an actual pore subunit [7].

Analytical, diagnostic and therapeutic context of TMEM142A

• Here we show that interaction between wild-type Stim and Orai, assessed by co-immunoprecipitation, is greatly enhanced after treatment with thapsigargin to induce Ca2+ store depletion [6].
• The cost-effectiveness analysis showed that mass screening strategies over 50 and 65 years of age and using ORAI were best [13].

References