6psd

Structural highlights

Function

EFC4B_HUMAN Ca(2+)-binding protein that plays a key role in store-operated Ca(2+) entry (SOCE) in T-cells by regulating CRAC channel activation. Acts as a cytoplasmic calcium-sensor that facilitates the clustering of ORAI1 and STIM1 at the junctional regions between the plasma membrane and the endoplasmic reticulum upon low Ca(2+) concentration. It thereby regulates CRAC channel activation, including translocation and clustering of ORAI1 and STIM1. Upon increase of cytoplasmic Ca(2+) resulting from opening of CRAC channels, dissociates from ORAI1 and STIM1, thereby destabilizing the ORAI1-STIM1 complex.^{[1] [2]} Rab GTPase that mediates the trafficking of Weibel-Palade bodies (WPBs) to microtubule organizing center (MTOC) in endothelial cells in response to acute inflammatory stimuli (PubMed:31092558). During histamine (but not thrombin) stimulation of endothelial cells, the dynein-bound form induces retrograde transport of a subset of WPBs along microtubules to the MTOC in a Ca(2+)-independent manner and its GTPase activity is essential for this function (PubMed:31092558). Ca(2+)-regulated dynein adapter protein that activates dynein-mediated transport and dynein-dynactin motility on microtubules and regulates endosomal trafficking of CD47 (PubMed:30814157). Acts as an intracellular signaling module bridging two important T-cell receptor (TCR) signaling pathways, Ca(2+)-NFAT and JNK, to affect T-cell activation (PubMed:27016526). In resting T-cells, is predominantly localized near TGN network in a GTP-bound form, upon TCR stimulation, localizes at the immunological synapse via interaction with VAV1 to activate downstream Ca(2+)-NFAT and JNK signaling pathways (PubMed:27016526). Plays a role in T-helper 1 (Th1) cell differentiation and T-helper 17 (Th17) cell effector function (PubMed:29987160). Plays a role in store-operated Ca(2+) entry (SOCE) in T-cells by regulating CRAC channel activation (PubMed:27016526).^{[3] [4] [5] [6]}

References

1. ↑ Srikanth S, Jung HJ, Kim KD, Souda P, Whitelegge J, Gwack Y. A novel EF-hand protein, CRACR2A, is a cytosolic Ca2+ sensor that stabilizes CRAC channels in T cells. Nat Cell Biol. 2010 May;12(5):436-46. PMID:20418871 doi:10.1038/ncb2045
2. ↑ Srikanth S, Kim KD, Gao Y, Woo JS, Ghosh S, Calmettes G, Paz A, Abramson J, Jiang M, Gwack Y. A large Rab GTPase encoded by CRACR2A is a component of subsynaptic vesicles that transmit T cell activation signals. Sci Signal. 2016 Mar 22;9(420):ra31. PMID:27016526 doi:10.1126/scisignal.aac9171
3. ↑ Srikanth S, Kim KD, Gao Y, Woo JS, Ghosh S, Calmettes G, Paz A, Abramson J, Jiang M, Gwack Y. A large Rab GTPase encoded by CRACR2A is a component of subsynaptic vesicles that transmit T cell activation signals. Sci Signal. 2016 Mar 22;9(420):ra31. PMID:27016526 doi:10.1126/scisignal.aac9171
4. ↑ Woo JS, Srikanth S, Kim KD, Elsaesser H, Lu J, Pellegrini M, Brooks DG, Sun Z, Gwack Y. CRACR2A-Mediated TCR Signaling Promotes Local Effector Th1 and Th17 Responses. J Immunol. 2018 Aug 15;201(4):1174-1185. PMID:29987160 doi:10.4049/jimmunol.1800659
5. ↑ Wang Y, Huynh W, Skokan TD, Lu W, Weiss A, Vale RD. CRACR2a is a calcium-activated dynein adaptor protein that regulates endocytic traffic. J Cell Biol. 2019 May 6;218(5):1619-1633. PMID:30814157 doi:10.1083/jcb.201806097
6. ↑ Miteva KT, Pedicini L, Wilson LA, Jayasinghe I, Slip RG, Marszalek K, Gaunt HJ, Bartoli F, Deivasigamani S, Sobradillo D, Beech DJ, McKeown L. Rab46 integrates Ca(2+) and histamine signaling to regulate selective cargo release from Weibel-Palade bodies. J Cell Biol. 2019 Jul 1;218(7):2232-2246. PMID:31092558 doi:10.1083/jcb.201810118