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'''Unreleased structure'''


The entry 2m1w is ON HOLD  until sometime in the future
==TICAM-2 TIR domain==
<StructureSection load='2m1w' size='340' side='right'caption='[[2m1w]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2m1w]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2M1W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2M1W FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=2m1w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2m1w OCA], [https://pdbe.org/2m1w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2m1w RCSB], [https://www.ebi.ac.uk/pdbsum/2m1w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2m1w 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 ==
Homotypic and heterotypic interactions between Toll/interleukin-1 receptor (TIR) domains in Toll-like receptors (TLRs) and downstream adaptors are essential to evoke innate immune responses. However, such oligomerization properties present intrinsic difficulties in structural studies of TIR domains. Here, using BB-loop mutations that disrupt homotypic interactions, we determined the structures of the monomeric TIR domain-containing adaptor molecule (TICAM)-1 and TICAM-2 TIR domains. Docking of the monomeric structures, together with yeast two hybrid-based mutagenesis assays, reveals that the homotypic interaction between TICAM-2 TIR is indispensable to present a scaffold for recruiting the monomeric moiety of the TICAM-1 TIR dimer. This result proposes a unique idea that oligomerization of upstream TIR domains is crucial for binding of downstream TIR domains. Furthermore, the bivalent nature of each TIR domain dimer can generate a large signaling complex under the activated TLRs, which would recruit downstream signaling molecules efficiently. This model is consistent with previous reports that BB-loop mutants completely abrogate downstream signaling.


Authors: Enokizono, Y., Kumeta, H., Funami, K., Horiuchi, M., Sarmiento, J., Yamashita, K., Standley, D.M., Matsumoto, M., Seya, T., Inagaki, F.
Structures and interface mapping of the TIR domain-containing adaptor molecules involved in interferon signaling.,Enokizono Y, Kumeta H, Funami K, Horiuchi M, Sarmiento J, Yamashita K, Standley DM, Matsumoto M, Seya T, Inagaki F Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19908-13. doi:, 10.1073/pnas.1222811110. Epub 2013 Nov 19. PMID:24255114<ref>PMID:24255114</ref>


Description: TICAM-2 TIR domain
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2m1w" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[TIR domain-containing adapter protein|TIR domain-containing adapter protein]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Enokizono Y]]
[[Category: Funami K]]
[[Category: Horiuchi M]]
[[Category: Inagaki F]]
[[Category: Kumeta H]]
[[Category: Matsumoto M]]
[[Category: Sarmiento J]]
[[Category: Seya T]]
[[Category: Standley DM]]
[[Category: Yamashita K]]

Latest revision as of 08:57, 15 May 2024

TICAM-2 TIR domainTICAM-2 TIR domain

Structural highlights

2m1w is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.[1] [2] [3] [4] [5] [6] [7] 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.[8] [9] [10] [11] [12] [13] [14]

Publication Abstract from PubMed

Homotypic and heterotypic interactions between Toll/interleukin-1 receptor (TIR) domains in Toll-like receptors (TLRs) and downstream adaptors are essential to evoke innate immune responses. However, such oligomerization properties present intrinsic difficulties in structural studies of TIR domains. Here, using BB-loop mutations that disrupt homotypic interactions, we determined the structures of the monomeric TIR domain-containing adaptor molecule (TICAM)-1 and TICAM-2 TIR domains. Docking of the monomeric structures, together with yeast two hybrid-based mutagenesis assays, reveals that the homotypic interaction between TICAM-2 TIR is indispensable to present a scaffold for recruiting the monomeric moiety of the TICAM-1 TIR dimer. This result proposes a unique idea that oligomerization of upstream TIR domains is crucial for binding of downstream TIR domains. Furthermore, the bivalent nature of each TIR domain dimer can generate a large signaling complex under the activated TLRs, which would recruit downstream signaling molecules efficiently. This model is consistent with previous reports that BB-loop mutants completely abrogate downstream signaling.

Structures and interface mapping of the TIR domain-containing adaptor molecules involved in interferon signaling.,Enokizono Y, Kumeta H, Funami K, Horiuchi M, Sarmiento J, Yamashita K, Standley DM, Matsumoto M, Seya T, Inagaki F Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19908-13. doi:, 10.1073/pnas.1222811110. Epub 2013 Nov 19. PMID:24255114[15]

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

See Also

References

  1. ↑ Bin LH, Xu LG, Shu HB. TIRP, a novel Toll/interleukin-1 receptor (TIR) domain-containing adapter protein involved in TIR signaling. J Biol Chem. 2003 Jul 4;278(27):24526-32. Epub 2003 Apr 28. PMID:12721283 doi:http://dx.doi.org/10.1074/jbc.M303451200
  2. ↑ Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya T. TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. J Biol Chem. 2003 Dec 12;278(50):49751-62. Epub 2003 Sep 30. PMID:14519765 doi:http://dx.doi.org/10.1074/jbc.M305820200
  3. ↑ Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E, Monks B, Pitha PM, Golenbock DT. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med. 2003 Oct 6;198(7):1043-55. Epub 2003 Sep 29. PMID:14517278 doi:http://dx.doi.org/10.1084/jem.20031023
  4. ↑ . PMID:194121844
  5. ↑ Rowe DC, McGettrick AF, Latz E, Monks BG, Gay NJ, Yamamoto M, Akira S, O'Neill LA, Fitzgerald KA, Golenbock DT. The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6299-304. Epub 2006 Apr 7. PMID:16603631 doi:http://dx.doi.org/10.1073/pnas.0510041103
  6. ↑ McGettrick AF, Brint EK, Palsson-McDermott EM, Rowe DC, Golenbock DT, Gay NJ, Fitzgerald KA, O'Neill LA. Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9196-201. Epub 2006 Jun 6. PMID:16757566 doi:http://dx.doi.org/10.1073/pnas.0600462103
  7. ↑ Ohnishi H, Tochio H, Kato Z, Kawamoto N, Kimura T, Kubota K, Yamamoto T, Funasaka T, Nakano H, Wong RW, Shirakawa M, Kondo N. TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88. PLoS One. 2012;7(6):e38423. doi: 10.1371/journal.pone.0038423. Epub 2012 Jun 7. PMID:22685567 doi:http://dx.doi.org/10.1371/journal.pone.0038423
  8. ↑ Bin LH, Xu LG, Shu HB. TIRP, a novel Toll/interleukin-1 receptor (TIR) domain-containing adapter protein involved in TIR signaling. J Biol Chem. 2003 Jul 4;278(27):24526-32. Epub 2003 Apr 28. PMID:12721283 doi:http://dx.doi.org/10.1074/jbc.M303451200
  9. ↑ Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya T. TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. J Biol Chem. 2003 Dec 12;278(50):49751-62. Epub 2003 Sep 30. PMID:14519765 doi:http://dx.doi.org/10.1074/jbc.M305820200
  10. ↑ Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E, Monks B, Pitha PM, Golenbock DT. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med. 2003 Oct 6;198(7):1043-55. Epub 2003 Sep 29. PMID:14517278 doi:http://dx.doi.org/10.1084/jem.20031023
  11. ↑ . PMID:194121844
  12. ↑ Rowe DC, McGettrick AF, Latz E, Monks BG, Gay NJ, Yamamoto M, Akira S, O'Neill LA, Fitzgerald KA, Golenbock DT. The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6299-304. Epub 2006 Apr 7. PMID:16603631 doi:http://dx.doi.org/10.1073/pnas.0510041103
  13. ↑ McGettrick AF, Brint EK, Palsson-McDermott EM, Rowe DC, Golenbock DT, Gay NJ, Fitzgerald KA, O'Neill LA. Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9196-201. Epub 2006 Jun 6. PMID:16757566 doi:http://dx.doi.org/10.1073/pnas.0600462103
  14. ↑ Ohnishi H, Tochio H, Kato Z, Kawamoto N, Kimura T, Kubota K, Yamamoto T, Funasaka T, Nakano H, Wong RW, Shirakawa M, Kondo N. TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88. PLoS One. 2012;7(6):e38423. doi: 10.1371/journal.pone.0038423. Epub 2012 Jun 7. PMID:22685567 doi:http://dx.doi.org/10.1371/journal.pone.0038423
  15. ↑ Enokizono Y, Kumeta H, Funami K, Horiuchi M, Sarmiento J, Yamashita K, Standley DM, Matsumoto M, Seya T, Inagaki F. Structures and interface mapping of the TIR domain-containing adaptor molecules involved in interferon signaling. Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19908-13. doi:, 10.1073/pnas.1222811110. Epub 2013 Nov 19. PMID:24255114 doi:http://dx.doi.org/10.1073/pnas.1222811110
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