6vsj

Structural highlights

Function

[SPIKE_CVMA5] S1 attaches the virion to the cell membrane by interacting with murine CEACAM1, initiating the infection.^[1] S2 is a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and plasma cell membranes. Presumably interacts with target cell lipid raft after cell attachment.^[2] [CEAM1_MOUSE] Cell adhesion protein that mediates homophilic cell adhesion in a calcium-independent manner (By similarity). Plays a role as coinhibitory receptor in immune response, insulin action and functions also as an activator during angiogenesis (PubMed:16680193, PubMed:17081782, PubMed:18544705, PubMed:21029969, PubMed:21081647, PubMed:22496641, PubMed:22962327, PubMed:23696226). Its coinhibitory receptor function is phosphorylation- and PTPN6 -dependent, which in turn, suppress signal transduction of associated receptors by dephosphorylation of their downstream effectors (PubMed:17081782, PubMed:21029969, PubMed:22496641). Plays a role in immune response, of T-cells, natural killer (NK) and neutrophils (PubMed:17081782, PubMed:23696226, PubMed:22496641, PubMed:21029969). Upon TCR/CD3 complex stimulation, inhibits TCR-mediated cytotoxicity by blocking granule exocytosis by mediating homophilic binding to adjacent cells, allowing interaction with and phosphorylation by LCK and interaction with the TCR/CD3 complex which recruits PTPN6 resulting in dephosphorylation of CD247 and ZAP70 (PubMed:22496641). Also inhibits T-cell proliferation and cytokine production through inhibition of JNK cascade and plays a crucial role in regulating autoimmunity and anti-tumor immunity by inhibiting T-cell through its interaction with HAVCR2 (PubMed:17081782). Upon natural killer (NK) cells activation, inhibit KLRK1-mediated cytolysis of CEACAM1-bearing tumor cells by trans-homophilic interactions with CEACAM1 on the target cell and lead to cis-interaction between CEACAM1 and KLRK1, allowing PTPN6 recruitment and then VAV1 dephosphorylation (PubMed:23696226). Upon neutrophils activation negatively regulates IL1B production by recruiting PTPN6 to a SYK-TLR4-CEACAM1 complex, that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome (PubMed:22496641). Downregulates neutrophil production by acting as a coinhibitory receptor for CSF3R by downregulating the CSF3R-STAT3 pathway through recruitment of PTPN6 that dephosphorylates CSF3R (PubMed:21029969). Also regulates insulin action by promoting INS clearance and regulating lipogenesis in liver through regulating insulin signaling (PubMed:18544705). Upon INS stimulation, undergoes phosphorylation by INSR leading to INS clearance by increasing receptor-mediated insulin endocytosis. This inernalization promotes interaction with FASN leading to receptor-mediated insulin degradation and to reduction of FASN activity leading to negative regulation of fatty acid synthesis. INSR-mediated phosphorylation also provokes a down-regulation of cell proliferation through SHC1 interaction resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 and phosphatidylinositol 3-kinase pathways (By similarity). Functions as activator in angiogenesis by promoting blood vessel remodeling through endothelial cell differentiation and migration and in arteriogenesis by increasing the number of collateral arteries and collateral vessel calibers after ischemia (PubMed:16680193, PubMed:22962327). Also regulates vascular permeability through the VEGFR2 signaling pathway resulting in control of nitric oxide production (PubMed:21081647). Downregulates cell growth in response to EGF through its interaction with SHC1 that mediates interaction with EGFR resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 pathway (PubMed:15467833). Negatively regulates platelet aggregation by decreasing platelet adhesion on type I collagen through the GPVI-FcRgamma complex (PubMed:19008452). Inhibits cell migration and cell scattering through interaction with FLNA; interfers with the interaction of FLNA with RALA (By similarity). Mediates bile acid transport activity in a phosphorylation dependent manner (By similarity). Negatively regulates osteoclastogenesis (PubMed:25490771).[UniProtKB:P13688][UniProtKB:P16573]^{[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]} Cell adhesion protein that mediates homophilic cell adhesion in a calcium-independent manner (PubMed:1633107). Promotes populations of T-cells regulating IgA production and secretion associated with control of the commensal microbiota and resistance to enteropathogens (PubMed:23123061).^{[14] [15]} (Microbial infection) In case of murine coronavirus (MHV) infection, serves as receptor for MHV S1 spike glycoprotein.^{[16] [17]}

References

1. ↑ Choi KS, Aizaki H, Lai MM. Murine coronavirus requires lipid rafts for virus entry and cell-cell fusion but not for virus release. J Virol. 2005 Aug;79(15):9862-71. PMID:16014947 doi:http://dx.doi.org/79/15/9862
2. ↑ Choi KS, Aizaki H, Lai MM. Murine coronavirus requires lipid rafts for virus entry and cell-cell fusion but not for virus release. J Virol. 2005 Aug;79(15):9862-71. PMID:16014947 doi:http://dx.doi.org/79/15/9862
3. ↑ Abou-Rjaily GA, Lee SJ, May D, Al-Share QY, Deangelis AM, Ruch RJ, Neumaier M, Kalthoff H, Lin SH, Najjar SM. CEACAM1 modulates epidermal growth factor receptor--mediated cell proliferation. J Clin Invest. 2004 Oct;114(7):944-52. doi: 10.1172/JCI21786. PMID:15467833 doi:http://dx.doi.org/10.1172/JCI21786
4. ↑ Horst AK, Ito WD, Dabelstein J, Schumacher U, Sander H, Turbide C, Brummer J, Meinertz T, Beauchemin N, Wagener C. Carcinoembryonic antigen-related cell adhesion molecule 1 modulates vascular remodeling in vitro and in vivo. J Clin Invest. 2006 Jun;116(6):1596-605. doi: 10.1172/JCI24340. Epub 2006 May 4. PMID:16680193 doi:http://dx.doi.org/10.1172/JCI24340
5. ↑ Nagaishi T, Pao L, Lin SH, Iijima H, Kaser A, Qiao SW, Chen Z, Glickman J, Najjar SM, Nakajima A, Neel BG, Blumberg RS. SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms. Immunity. 2006 Nov;25(5):769-81. doi: 10.1016/j.immuni.2006.08.026. Epub 2006 Nov, 2. PMID:17081782 doi:http://dx.doi.org/10.1016/j.immuni.2006.08.026
6. ↑ DeAngelis AM, Heinrich G, Dai T, Bowman TA, Patel PR, Lee SJ, Hong EG, Jung DY, Assmann A, Kulkarni RN, Kim JK, Najjar SM. Carcinoembryonic antigen-related cell adhesion molecule 1: a link between insulin and lipid metabolism. Diabetes. 2008 Sep;57(9):2296-303. doi: 10.2337/db08-0379. Epub 2008 Jun 10. PMID:18544705 doi:http://dx.doi.org/10.2337/db08-0379
7. ↑ Wong C, Liu Y, Yip J, Chand R, Wee JL, Oates L, Nieswandt B, Reheman A, Ni H, Beauchemin N, Jackson DE. CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo. Blood. 2009 Feb 19;113(8):1818-28. doi: 10.1182/blood-2008-06-165043. Epub 2008, Nov 13. PMID:19008452 doi:http://dx.doi.org/10.1182/blood-2008-06-165043
8. ↑ Pan H, Shively JE. Carcinoembryonic antigen-related cell adhesion molecule-1 regulates granulopoiesis by inhibition of granulocyte colony-stimulating factor receptor. Immunity. 2010 Oct 29;33(4):620-31. doi: 10.1016/j.immuni.2010.10.009. PMID:21029969 doi:http://dx.doi.org/10.1016/j.immuni.2010.10.009
9. ↑ Nouvion AL, Oubaha M, Leblanc S, Davis EC, Jastrow H, Kammerer R, Breton V, Turbide C, Ergun S, Gratton JP, Beauchemin N. CEACAM1: a key regulator of vascular permeability. J Cell Sci. 2010 Dec 15;123(Pt 24):4221-30. doi: 10.1242/jcs.073635. Epub 2010, Nov 16. PMID:21081647 doi:http://dx.doi.org/10.1242/jcs.073635
10. ↑ Lu R, Pan H, Shively JE. CEACAM1 negatively regulates IL-1beta production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex. PLoS Pathog. 2012;8(4):e1002597. doi: 10.1371/journal.ppat.1002597. Epub 2012 Apr, 5. PMID:22496641 doi:http://dx.doi.org/10.1371/journal.ppat.1002597
11. ↑ Bickert T, Marshall RP, Zhang Z, Ludewig P, Binder M, Klinke A, Rottbauer W, Amling M, Wagener C, Ito WD, Horst AK. Acceleration of collateral development by carcinoembryonic antigen-related cell adhesion molecule 1 expression on CD11b/(+)Gr-1(+) myeloid cells--brief report. Arterioscler Thromb Vasc Biol. 2012 Nov;32(11):2566-8. doi:, 10.1161/ATVBAHA.112.300015. Epub 2012 Sep 6. PMID:22962327 doi:http://dx.doi.org/10.1161/ATVBAHA.112.300015
12. ↑ Hosomi S, Chen Z, Baker K, Chen L, Huang YH, Olszak T, Zeissig S, Wang JH, Mandelboim O, Beauchemin N, Lanier LL, Blumberg RS. CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling. Eur J Immunol. 2013 Sep;43(9):2473-83. doi: 10.1002/eji.201242676. Epub 2013 Jun , 18. PMID:23696226 doi:http://dx.doi.org/10.1002/eji.201242676
13. ↑ Heckt T, Bickert T, Jeschke A, Seitz S, Schulze J, Ito WD, Zimmermann W, Amling M, Schinke T, Horst AK, Keller J. Increased osteoclastogenesis in mice lacking the carcinoembryonic antigen-related cell adhesion molecule 1. PLoS One. 2014 Dec 9;9(12):e114360. doi: 10.1371/journal.pone.0114360., eCollection 2014. PMID:25490771 doi:http://dx.doi.org/10.1371/journal.pone.0114360
14. ↑ McCuaig K, Turbide C, Beauchemin N. mmCGM1a: a mouse carcinoembryonic antigen gene family member, generated by alternative splicing, functions as an adhesion molecule. Cell Growth Differ. 1992 Mar;3(3):165-74. PMID:1633107
15. ↑ Chen L, Chen Z, Baker K, Halvorsen EM, da Cunha AP, Flak MB, Gerber G, Huang YH, Hosomi S, Arthur JC, Dery KJ, Nagaishi T, Beauchemin N, Holmes KV, Ho JW, Shively JE, Jobin C, Onderdonk AB, Bry L, Weiner HL, Higgins DE, Blumberg RS. The short isoform of the CEACAM1 receptor in intestinal T cells regulates mucosal immunity and homeostasis via Tfh cell induction. Immunity. 2012 Nov 16;37(5):930-46. doi: 10.1016/j.immuni.2012.07.016. Epub 2012 , Nov 1. PMID:23123061 doi:http://dx.doi.org/10.1016/j.immuni.2012.07.016
16. ↑ Hemmila E, Turbide C, Olson M, Jothy S, Holmes KV, Beauchemin N. Ceacam1a-/- mice are completely resistant to infection by murine coronavirus mouse hepatitis virus A59. J Virol. 2004 Sep;78(18):10156-65. PMID:15331748 doi:http://dx.doi.org/10.1128/JVI.78.18.10156-10165.2004
17. ↑ Dveksler GS, Pensiero MN, Cardellichio CB, Williams RK, Jiang GS, Holmes KV, Dieffenbach CW. Cloning of the mouse hepatitis virus (MHV) receptor: expression in human and hamster cell lines confers susceptibility to MHV. J Virol. 1991 Dec;65(12):6881-91. PMID:1719235