3ulu

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Structure of quaternary complex of human TLR3ecd with three Fabs (Form1)

Structural highlights

3ulu is a 7 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.52Å
Ligands:BMA, MAN, NAG, SO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TLR3_HUMAN Defects in TLR3 are associated with herpes simplex encephalitis type 2 (HSE2) [MIM:613002. HSE is a rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. HSE is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Note=TLR3 mutations predispose otherwise healthy individuals to isolated herpes simplex encephalitis through a mechanism that involves impaired IFNs production and reduced immune defense against viral infection in the central nervous system.[1]

Function

TLR3_HUMAN Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.[2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

Toll-like receptor 3 (TLR3) recognizes dsRNA and initiates an innate immune response through the formation of a signaling unit (SU) composed of one double-stranded RNA (dsRNA) and two TLR3 molecules. We report the crystal structure of human TLR3 ectodomain (TLR3ecd) in a quaternary complex with three neutralizing Fab fragments. Fab15 binds an epitope that overlaps the C-terminal dsRNA binding site and, in biochemical assays, blocks the interaction of TLR3ecd with dsRNA, thus directly antagonizing TLR3 signaling through inhibition of SU formation. In contrast, Fab12 and Fab1068 bind TLR3ecd at sites distinct from the N- and C-terminal regions that interact with dsRNA and do not inhibit minimal SU formation with short dsRNA. Molecular modeling based on the co-structure rationalizes these observations by showing that both Fab12 and Fab1068 prevent lateral clustering of SUs along the length of the dsRNA ligand. This model is further supported by cell-based assay results using dsRNA ligands of lengths that support single and multiple SUs. Thus, their antagonism of TLR3 signaling indicates that lateral clustering of SUs is required for TLR3 signal transduction.

Lateral Clustering of TLR3:dsRNA Signaling Units Revealed by TLR3ecd:3Fabs Quaternary Structure.,Luo J, Obmolova G, Malia TJ, Wu SJ, Duffy KE, Marion JD, Bell JK, Ge P, Zhou ZH, Teplyakov A, Zhao Y, Lamb RJ, Jordan JL, San Mateo LR, Sweet RW, Gilliland GL J Mol Biol. 2012 May 9. PMID:22579623[8]

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

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Citations
11 reviews cite this structure
Assembly and localization of Toll-like receptor signalling complexes.
Gay et al. (2014)
10 more
15 other articles
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See Also

References

  1. ↑ Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, Segal D, Sancho-Shimizu V, Lorenzo L, Puel A, Picard C, Chapgier A, Plancoulaine S, Titeux M, Cognet C, von Bernuth H, Ku CL, Casrouge A, Zhang XX, Barreiro L, Leonard J, Hamilton C, Lebon P, Heron B, Vallee L, Quintana-Murci L, Hovnanian A, Rozenberg F, Vivier E, Geissmann F, Tardieu M, Abel L, Casanova JL. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007 Sep 14;317(5844):1522-7. PMID:17872438 doi:317/5844/1522
  2. ↑ de Bouteiller O, Merck E, Hasan UA, Hubac S, Benguigui B, Trinchieri G, Bates EE, Caux C. Recognition of double-stranded RNA by human toll-like receptor 3 and downstream receptor signaling requires multimerization and an acidic pH. J Biol Chem. 2005 Nov 18;280(46):38133-45. Epub 2005 Sep 6. PMID:16144834 doi:M507163200
  3. ↑ Johnsen IB, Nguyen TT, Ringdal M, Tryggestad AM, Bakke O, Lien E, Espevik T, Anthonsen MW. Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling. EMBO J. 2006 Jul 26;25(14):3335-46. Epub 2006 Jul 6. PMID:16858407 doi:7601222
  4. ↑ Bell JK, Askins J, Hall PR, Davies DR, Segal DM. The dsRNA binding site of human Toll-like receptor 3. Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8792-7. Epub 2006 May 23. PMID:16720699 doi:10.1073/pnas.0603245103
  5. ↑ Sarkar SN, Elco CP, Peters KL, Chattopadhyay S, Sen GC. Two tyrosine residues of Toll-like receptor 3 trigger different steps of NF-kappa B activation. J Biol Chem. 2007 Feb 9;282(6):3423-7. Epub 2006 Dec 18. PMID:17178723 doi:C600226200
  6. ↑ Leonard JN, Ghirlando R, Askins J, Bell JK, Margulies DH, Davies DR, Segal DM. The TLR3 signaling complex forms by cooperative receptor dimerization. Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):258-63. doi: 10.1073/pnas.0710779105., Epub 2008 Jan 2. PMID:18172197 doi:10.1073/pnas.0710779105
  7. ↑ Bell JK, Botos I, Hall PR, Askins J, Shiloach J, Segal DM, Davies DR. The molecular structure of the Toll-like receptor 3 ligand-binding domain. Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10976-80. Epub 2005 Jul 25. PMID:16043704
  8. ↑ Luo J, Obmolova G, Malia TJ, Wu SJ, Duffy KE, Marion JD, Bell JK, Ge P, Zhou ZH, Teplyakov A, Zhao Y, Lamb RJ, Jordan JL, San Mateo LR, Sweet RW, Gilliland GL. Lateral Clustering of TLR3:dsRNA Signaling Units Revealed by TLR3ecd:3Fabs Quaternary Structure. J Mol Biol. 2012 May 9. PMID:22579623 doi:10.1016/j.jmb.2012.05.006

Contents


PDB ID 3ulu

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