2mak | pdb_00002mak

Solution structure of the STIM1 CC1-CC2 homodimer in complex with two Orai1 C-terminal domains.

spinqualitylabelsall models 2mak, 20 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2mak is a 4 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 2maj Gene: STIM1, GOK (HUMAN), ORAI1, CRACM1, TMEM142A (HUMAN) Resources: FirstGlance, OCA, RCSB, PDBsum Disease [STIM1_HUMAN] Defects in STIM1 are the cause of immune dysfunction with T-cell inactivation due to calcium entry defect type 2 (IDTICED2) [MIM:612783]. IDTICED2 is an immune disorder characterized by recurrent infections, impaired T-cell activation and proliferative response, decreased T-cell production of cytokines, lymphadenopathy, and normal lymphocytes counts and serum immunoglobulin levels. Additional features include thrombocytopenia, autoimmune hemolytic anemia, non-progressive myopathy, partial iris hypoplasia, hepatosplenomegaly and defective enamel dentition. [CRCM1_HUMAN] Combined immunodeficiency due to ORAI1 deficiency. The disease is caused by mutations affecting the gene represented in this entry. Function [STIM1_HUMAN] Plays a role in mediating store-operated Ca(2+) entry (SOCE), a Ca(2+) influx following depletion of intracellular Ca(2+) stores. Acts as Ca(2+) sensor in the endoplasmic reticulum via its EF-hand domain. Upon Ca(2+) depletion, translocates from the endoplasmic reticulum to the plasma membrane where it activates the Ca(2+) release-activated Ca(2+) (CRAC) channel subunit, TMEM142A/ORAI1. [CRCM1_HUMAN] Ca(2+) release-activated Ca(2+) (CRAC) channel subunit which mediates Ca(2+) influx following depletion of intracellular Ca(2+) stores and channel activation by the Ca(2+) sensor, STIM1. CRAC channels are the main pathway for Ca(2+) influx in T-cells and promote the immune response to pathogens by activating the transcription factor NFAT. Publication Abstract from PubMed Orai1 calcium channels in the plasma membrane are activated by stromal interaction molecule-1 (STIM1), an endoplasmic reticulum calcium sensor, to mediate store-operated calcium entry (SOCE). The cytosolic region of STIM1 contains a long putative coiled-coil (CC)1 segment and shorter CC2 and CC3 domains. Here we present solution nuclear magnetic resonance structures of a trypsin-resistant CC1-CC2 fragment in the apo and Orai1-bound states. Each CC1-CC2 subunit forms a U-shaped structure that homodimerizes through antiparallel interactions between equivalent alpha-helices. The CC2:CC2' helix pair clamps two identical acidic Orai1 C-terminal helices at opposite ends of a hydrophobic/basic STIM-Orai association pocket. STIM1 mutants disrupting CC1:CC1' interactions attenuate, while variants promoting CC1 stability spontaneously activate Orai1 currents. CC2 mutations cause remarkable variability in Orai1 activation because of a dual function in binding Orai1 and autoinhibiting STIM1 oligomerization via interactions with CC3. We conclude that SOCE is activated through dynamic interplay between STIM1 and Orai1 helices. STIM1/Orai1 coiled-coil interplay in the regulation of store-operated calcium entry.,Stathopulos PB, Schindl R, Fahrner M, Zheng L, Gasmi-Seabrook GM, Muik M, Romanin C, Ikura M Nat Commun. 2013 Dec 19;4:2963. doi: 10.1038/ncomms3963. PMID:24351972 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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