Cryo-EM structure of human TLR7 in complex with UNC93B1
Structural highlights
7cyn is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
TLR7_HUMAN Systemic lupus erythematosus. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.
Function
TLR7_HUMAN Endosomal receptor that plays a key role in innate and adaptive immunity (PubMed:14976261, PubMed:32433612). Controls host immune response against pathogens through recognition of uridine-containing single strand RNAs (ssRNAs) of viral origin or guanosine analogs (PubMed:12738885, PubMed:27742543, PubMed:31608988, PubMed:32706371, PubMed:35477763). Upon binding to agonists, undergoes dimerization that brings TIR domains from the two molecules into direct contact, leading to the recruitment of TIR-containing downstream adapter MYD88 through homotypic interaction (PubMed:27742543). In turn, the Myddosome signaling complex is formed involving IRAK4, IRAK1, TRAF6, TRAF3 leading to activation of downstream transcription factors NF-kappa-B and IRF7 to induce pro-inflammatory cytokines and interferons, respectively (PubMed:27742543, PubMed:32706371).[1][2][3][4][5][6][7]
Publication Abstract from PubMed
Nucleic acid-sensing Toll-like receptors (TLRs) play a pivotal role in innate immunity by recognizing foreign DNA and RNA. Compartmentalization of these TLRs in the endosome limits their activation by self-derived nucleic acids and reduces the possibility of autoimmune reactions. Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. Here, we report two cryo-EM structures of human and mouse TLR3-UNC93B1 complexes and a human TLR7-UNC93B1 complex. UNC93B1 exhibits structural similarity to the major facilitator superfamily transporters. Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions, but the complexes of TLR3 and TLR7 with UNC93B1 differ in their oligomerization state. The structural information provided here should aid in designing compounds to combat autoimmune diseases.
Cryo-EM structures of Toll-like receptors in complex with UNC93B1.,Ishida H, Asami J, Zhang Z, Nishizawa T, Shigematsu H, Ohto U, Shimizu T Nat Struct Mol Biol. 2021 Feb;28(2):173-180. doi: 10.1038/s41594-020-00542-w. , Epub 2021 Jan 11. PMID:33432245[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Lee J, Chuang TH, Redecke V, She L, Pitha PM, Carson DA, Raz E, Cottam HB. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6646-51. PMID:12738885 doi:10.1073/pnas.0631696100
↑ Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004 Mar 5;303(5663):1529-31. PMID:14976261 doi:10.1126/science.1093616
↑ Zhang Z, Ohto U, Shibata T, Krayukhina E, Taoka M, Yamauchi Y, Tanji H, Isobe T, Uchiyama S, Miyake K, Shimizu T. Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA. Immunity. 2016 Oct 18;45(4):737-748. doi: 10.1016/j.immuni.2016.09.011. Epub 2016, Oct 11. PMID:27742543 doi:http://dx.doi.org/10.1016/j.immuni.2016.09.011
↑ Davenne T, Bridgeman A, Rigby RE, Rehwinkel J. Deoxyguanosine is a TLR7 agonist. Eur J Immunol. 2020 Jan;50(1):56-62. PMID:31608988 doi:10.1002/eji.201948151
↑ Heinz LX, Lee J, Kapoor U, Kartnig F, Sedlyarov V, Papakostas K, César-Razquin A, Essletzbichler P, Goldmann U, Stefanovic A, Bigenzahn JW, Scorzoni S, Pizzagalli MD, Bensimon A, Müller AC, King FJ, Li J, Girardi E, Mbow ML, Whitehurst CE, Rebsamen M, Superti-Furga G. TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. Nature. 2020 May;581(7808):316-322. PMID:32433612 doi:10.1038/s41586-020-2282-0
↑ van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, van Deuren RC, Steehouwer M, van Reijmersdal SV, Jaeger M, Hofste T, Astuti G, Corominas Galbany J, van der Schoot V, van der Hoeven H, Hagmolen Of Ten Have W, Klijn E, van den Meer C, Fiddelaers J, de Mast Q, Bleeker-Rovers CP, Joosten LAB, Yntema HG, Gilissen C, Nelen M, van der Meer JWM, Brunner HG, Netea MG, van de Veerdonk FL, Hoischen A. Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA. 2020 Aug 18;324(7):663-673. PMID:32706371 doi:10.1001/jama.2020.13719
↑ Brown GJ, Cañete PF, Wang H, Medhavy A, Bones J, Roco JA, He Y, Qin Y, Cappello J, Ellyard JI, Bassett K, Shen Q, Burgio G, Zhang Y, Turnbull C, Meng X, Wu P, Cho E, Miosge LA, Andrews TD, Field MA, Tvorogov D, Lopez AF, Babon JJ, López CA, Gónzalez-Murillo Á, Garulo DC, Pascual V, Levy T, Mallack EJ, Calame DG, Lotze T, Lupski JR, Ding H, Ullah TR, Walters GD, Koina ME, Cook MC, Shen N, de Lucas Collantes C, Corry B, Gantier MP, Athanasopoulos V, Vinuesa CG. TLR7 gain-of-function genetic variation causes human lupus. Nature. 2022 May;605(7909):349-356. PMID:35477763 doi:10.1038/s41586-022-04642-z
↑ Ishida H, Asami J, Zhang Z, Nishizawa T, Shigematsu H, Ohto U, Shimizu T. Cryo-EM structures of Toll-like receptors in complex with UNC93B1. Nat Struct Mol Biol. 2021 Feb;28(2):173-180. PMID:33432245 doi:10.1038/s41594-020-00542-w
