Tmem110

Definition and cellular localization

TMEM110, also designated as STIMATE[1] (for STIM-activating enhancer), is an ER-resident multi-transmembrane protein identified through a proteomic study on the ER-PM junctions. The ER-PM junctions are defined as specialized junctional sites, also known as membrane contact sites, that connect the endoplasmic reticulum (ER) and the plasma membrane (PM), and are closely implicated in controlling lipid and calcium homeostasis in mammalian cells.[2]

Function

TMEM110 is a positive modulator of calcium flux mediated by the STIM-ORAI signaling in vertebrates.[1] STIMATE can physically associate with STIM1 to promote conformational switch of STIM1 from inactive toward an activated state,[3][4] thereby coupling to and gating the ORAI calcium channels on the plasma membrane.

Depletion of TMEM110 with RNAi knockdown or Cas9-mediated gene disruption substantially reduces the puncta formation of STIM1 at ER-PM junctions and remarkably inhibits the calcium/calcineurin/NFAT signaling axis.[5][6] More genetic and biochemical studies are needed to uncover more uncharted functions of this ER-resident protein at ER-PM junctions.

References
  1. Jing, Ji; He, Lian; Sun, Aomin; Quintana, Ariel; Ding, Yuehe; Ma, Guolin; Tan, Peng; Liang, Xiaowen; Zheng, Xiaolu (2015-01-01). "Proteomic mapping of ER–PM junctions identifies STIMATE as a regulator of Ca2+ influx". Nature Cell Biology. 17 (10): 1339–47. doi:10.1038/ncb3234. PMC 4589512. PMID 26322679.
  2. Carrasco, Silvia; Meyer, Tobias (2011-01-01). "STIM Proteins and the Endoplasmic Reticulum-Plasma Membrane Junctions". Annual Review of Biochemistry. 80 (1): 973–1000. doi:10.1146/annurev-biochem-061609-165311. PMC 3897197. PMID 21548779.
  3. Zhou, Yubin; Srinivasan, Prasanna; Razavi, Shiva; Seymour, Sam; Meraner, Paul; Gudlur, Aparna; Stathopulos, Peter B; Ikura, Mitsuhiko; Rao, Anjana (2013-01-01). "Initial activation of STIM1, the regulator of store-operated calcium entry". Nature Structural & Molecular Biology. 20 (8): 973–981. doi:10.1038/nsmb.2625. PMC 3784406. PMID 23851458.
  4. Ma, Guolin; Wei, Ming; He, Lian; Liu, Chongxu; Wu, Bo; Zhang, Shenyuan L.; Jing, Ji; Liang, Xiaowen; Senes, Alessandro (2015-07-17). "Inside-out Ca2+ signalling prompted by STIM1 conformational switch". Nature Communications. 6: 7826. Bibcode:2015NatCo...6.7826M. doi:10.1038/ncomms8826. PMC 4509486. PMID 26184105.
  5. Müller, Martin R.; Rao, Anjana (2010-01-01). "NFAT, immunity and cancer: a transcription factor comes of age". Nature Reviews Immunology. 10 (9): 645–656. doi:10.1038/nri2818. PMID 20725108. S2CID 29256284.
  6. Oh-hora, Masatsugu; Rao, Anjana (2008-01-01). "Calcium signaling in lymphocytes". Current Opinion in Immunology. 20 (3): 250–258. doi:10.1016/j.coi.2008.04.004. PMC 2574011. PMID 18515054.
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