2k60

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NMR structure of calcium-loaded STIM1 EF-SAMNMR structure of calcium-loaded STIM1 EF-SAM

Structural highlights

2k60 is a 1 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:STIM1, GOK (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.[1]

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.[2] [3] [4] [5] [6] [7] [8] [9] [10]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Stromal interaction molecule-1 (STIM1) activates store-operated Ca2+ entry (SOCE) in response to diminished luminal Ca2+ levels. Here, we present the atomic structure of the Ca2+-sensing region of STIM1 consisting of the EF-hand and sterile alpha motif (SAM) domains (EF-SAM). The canonical EF-hand is paired with a previously unidentified EF-hand. Together, the EF-hand pair mediates mutually indispensable hydrophobic interactions between the EF-hand and SAM domains. Structurally critical mutations in the canonical EF-hand, "hidden" EF-hand, or SAM domain disrupt Ca2+ sensitivity in oligomerization via destabilization of the entire EF-SAM entity. In mammalian cells, EF-SAM destabilization mutations within full-length STIM1 induce punctae formation and activate SOCE independent of luminal Ca2+. We provide atomic resolution insight into the molecular basis for STIM1-mediated SOCE initiation and show that the folded/unfolded state of the Ca2+-sensing region of STIM is crucial to SOCE regulation.

Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry.,Stathopulos PB, Zheng L, Li GY, Plevin MJ, Ikura M Cell. 2008 Oct 3;135(1):110-22. PMID:18854159[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Picard C, McCarl CA, Papolos A, Khalil S, Luthy K, Hivroz C, LeDeist F, Rieux-Laucat F, Rechavi G, Rao A, Fischer A, Feske S. STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N Engl J Med. 2009 May 7;360(19):1971-80. doi: 10.1056/NEJMoa0900082. PMID:19420366 doi:http://dx.doi.org/10.1056/NEJMoa0900082
  2. ↑ Sabbioni S, Barbanti-Brodano G, Croce CM, Negrini M. GOK: a gene at 11p15 involved in rhabdomyosarcoma and rhabdoid tumor development. Cancer Res. 1997 Oct 15;57(20):4493-7. PMID:9377559
  3. ↑ Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol. 2005 Jul 12;15(13):1235-41. PMID:16005298 doi:10.1016/j.cub.2005.05.055
  4. ↑ Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol. 2005 May 9;169(3):435-45. Epub 2005 May 2. PMID:15866891 doi:jcb.200502019
  5. ↑ Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature. 2005 Oct 6;437(7060):902-5. PMID:16208375 doi:nature04147
  6. ↑ Mercer JC, Dehaven WI, Smyth JT, Wedel B, Boyles RR, Bird GS, Putney JW Jr. Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J Biol Chem. 2006 Aug 25;281(34):24979-90. Epub 2006 Jun 28. PMID:16807233 doi:M604589200
  7. ↑ Soboloff J, Spassova MA, Tang XD, Hewavitharana T, Xu W, Gill DL. Orai1 and STIM reconstitute store-operated calcium channel function. J Biol Chem. 2006 Jul 28;281(30):20661-5. Epub 2006 Jun 9. PMID:16766533 doi:10.1074/jbc.C600126200
  8. ↑ Peinelt C, Vig M, Koomoa DL, Beck A, Nadler MJ, Koblan-Huberson M, Lis A, Fleig A, Penner R, Kinet JP. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol. 2006 Jul;8(7):771-3. Epub 2006 May 30. PMID:16733527 doi:ncb1435
  9. ↑ Spassova MA, Soboloff J, He LP, Xu W, Dziadek MA, Gill DL. STIM1 has a plasma membrane role in the activation of store-operated Ca(2+) channels. Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4040-5. Epub 2006 Mar 6. PMID:16537481 doi:0510050103
  10. ↑ Palty R, Raveh A, Kaminsky I, Meller R, Reuveny E. SARAF inactivates the store operated calcium entry machinery to prevent excess calcium refilling. Cell. 2012 Apr 13;149(2):425-38. doi: 10.1016/j.cell.2012.01.055. Epub 2012 Mar, 29. PMID:22464749 doi:10.1016/j.cell.2012.01.055
  11. ↑ Stathopulos PB, Zheng L, Li GY, Plevin MJ, Ikura M. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell. 2008 Oct 3;135(1):110-22. PMID:18854159 doi:10.1016/j.cell.2008.08.006
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