View source for 9dki


==Crystal structure of the TIR domain C117H mutant from human TRAM==
<StructureSection load='9dki' size='340' side='right'caption='[[9dki]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9dki]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9DKI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9DKI FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9dki FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9dki OCA], [https://pdbe.org/9dki PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9dki RCSB], [https://www.ebi.ac.uk/pdbsum/9dki PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9dki ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TCAM2_HUMAN TCAM2_HUMAN] Functions as sorting adapter in LPS-TLR4 signaling to regulate the MYD88-independent pathway during the innate immune response to LPS. Physically bridges TLR4 and TICAM1 and functionally transmits LPS-TRL4 signal to TICAM1; signaling is proposed to occur in early endosomes after endocytosis of TLR4. May also be involved in IL1-triggered NF-kappa-B activation, functioning upstream of IRAK1, IRAK2, TRAF6, and IKBKB; however, reports are controversial. Involved in IL-18 signaling and is proposed to function as a sorting adaptor for MYD88 in IL-18 signaling during adaptive immune response.<ref>PMID:12721283</ref> <ref>PMID:14519765</ref> <ref>PMID:14517278</ref> <ref>PMID:194121844</ref> <ref>PMID:16603631</ref> <ref>PMID:16757566</ref> <ref>PMID:22685567</ref>   Isoform 2: Proposed to inhibit LPS-TLR4 signaling at the late endosome by interaction with isoform 1 thereby disrupting the association of isoform 1 with TICAM1. May be involved in TLR4 degradation in late endosomes.<ref>PMID:12721283</ref> <ref>PMID:14519765</ref> <ref>PMID:14517278</ref> <ref>PMID:194121844</ref> <ref>PMID:16603631</ref> <ref>PMID:16757566</ref> <ref>PMID:22685567</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Innate immunity relies on Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns. The TIR (Toll/interleukin-1 receptor) domain-containing TLR adaptors TRIF (TIR domain-containing adaptor-inducing interferon-beta) and TRAM (TRIF-related adaptor molecule) are essential for MyD88-independent TLR signaling. However, the structural basis of TRIF and TRAM TIR domain-based signaling remains unclear. Here, we present cryo-EM structures of filaments formed by TRIF and TRAM TIR domains at resolutions of 3.3 A and 5.6 A, respectively. Both structures reveal two-stranded parallel helical arrangements. Functional studies underscore the importance of intrastrand interactions, mediated by the BB-loop, and interstrand interactions in TLR4-mediated signaling. We also report the crystal structure of the monomeric TRAM TIR domain bearing the BB loop mutation C117H, which reveals conformational differences consistent with its inactivity. Our findings suggest a unified signaling mechanism by the TIR domains of the four signaling TLR adaptors MyD88, MAL, TRIF, and TRAM and reveal potential therapeutic targets for immunity-related disorders.

Structural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM.,Manik MK, Pan M, Xiao L, Gu W, Kim H, Pospich S, Hedger A, Vajjhala PR, Lee MYL, Qian X, Landsberg MJ, Ve T, Nanson JD, Raunser S, Stacey KJ, Wu H, Kobe B Proc Natl Acad Sci U S A. 2025 Jan 14;122(2):e2418988122. doi: , 10.1073/pnas.2418988122. Epub 2025 Jan 9. PMID:39786929<ref>PMID:39786929</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9dki" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Gu W]]
[[Category: Kobe B]]
[[Category: Nanson JD]]
[[Category: Pan M]]