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2ndh

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NMR solution structure of MAL/TIRAP TIR domain (C116A)

Structural highlights

2ndh 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.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TIRAP_HUMAN Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha and interleukin-6.^[1] ^[2]

Publication Abstract from PubMed

MyD88 adaptor-like (MAL) is a critical protein in innate immunity, involved in signaling by several Toll-like receptors (TLRs), key pattern recognition receptors (PRRs). Crystal structures of MAL revealed a nontypical Toll/interleukin-1 receptor (TIR)-domain fold stabilized by two disulfide bridges. We therefore undertook a structural and functional analysis of the role of reactive cysteine residues in the protein. Under reducing conditions, the cysteines do not form disulfides, but under oxidizing conditions they are highly amenable to modification. The solution structure of the reduced form of the MAL TIR domain, determined by NMR spectroscopy, reveals a remarkable structural rearrangement compared with the disulfide-bonded structure, which includes the relocation of a beta-strand and repositioning of the functionally important "BB-loop" region to a location more typical for TIR domains. Redox measurements by NMR further reveal that C91 has the highest redox potential of all cysteines in MAL. Indeed, mass spectrometry revealed that C91 undergoes glutathionylation in macrophages activated with the TLR4 ligand lipopolysaccharide (LPS). The C91A mutation limits MAL glutathionylation and acts as a dominant negative, blocking the interaction of MAL with its downstream target MyD88. The H92P mutation mimics the dominant-negative effects of the C91A mutation, presumably by preventing C91 glutathionylation. The MAL C91A and H92P mutants also display diminished degradation and interaction with interleukin-1 receptor-associated kinase 4 (IRAK4). We conclude that in the cell, MAL is not disulfide-bonded and requires glutathionylation of C91 for signaling.

Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling.,Hughes MM, Lavrencic P, Coll RC, Ve T, Ryan DG, Williams NC, Menon D, Mansell A, Board PG, Mobli M, Kobe B, O'Neill LAJ Proc Natl Acad Sci U S A. 2017 Aug 8;114(32):E6480-E6489. doi:, 10.1073/pnas.1701868114. Epub 2017 Jul 24. PMID:28739909^[3]

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

References

↑ Semaan N, Alsaleh G, Gottenberg JE, Wachsmann D, Sibilia J. Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-talk between MyD88 and FAK pathways. J Immunol. 2008 Mar 1;180(5):3485-91. PMID:18292575
↑ Nagpal K, Plantinga TS, Wong J, Monks BG, Gay NJ, Netea MG, Fitzgerald KA, Golenbock DT. A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling. J Biol Chem. 2009 Sep 18;284(38):25742-8. doi: 10.1074/jbc.M109.014886. Epub 2009, Jun 9. PMID:19509286 doi:http://dx.doi.org/10.1074/jbc.M109.014886
↑ Hughes MM, Lavrencic P, Coll RC, Ve T, Ryan DG, Williams NC, Menon D, Mansell A, Board PG, Mobli M, Kobe B, O'Neill LAJ. Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling. Proc Natl Acad Sci U S A. 2017 Aug 8;114(32):E6480-E6489. doi:, 10.1073/pnas.1701868114. Epub 2017 Jul 24. PMID:28739909 doi:http://dx.doi.org/10.1073/pnas.1701868114

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2ndh"

Categories: Homo sapiens | Large Structures | Lavrencic P | Mobli M

@@ Line 1: / Line 1: @@
 ==NMR solution structure of MAL/TIRAP TIR domain (C116A)==
-<StructureSection load='2ndh' size='340' side='right'caption='[[2ndh]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='2ndh' size='340' side='right'caption='[[2ndh]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2ndh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NDH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2ndh]] 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=2NDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NDH FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2yp2|2yp2]], [[3ub2|3ub2]], [[4lqd|4lqd]], [[4fz5|4fz5]]</div></td></tr>
+</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=2ndh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ndh OCA], [https://pdbe.org/2ndh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ndh RCSB], [https://www.ebi.ac.uk/pdbsum/2ndh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ndh ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TIRAP, MAL ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=2ndh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ndh OCA], [https://pdbe.org/2ndh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ndh RCSB], [https://www.ebi.ac.uk/pdbsum/2ndh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ndh ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/TIRAP_HUMAN TIRAP_HUMAN]] Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha and interleukin-6.<ref>PMID:18292575</ref> <ref>PMID:19509286</ref>
+[https://www.uniprot.org/uniprot/TIRAP_HUMAN TIRAP_HUMAN] Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha and interleukin-6.<ref>PMID:18292575</ref> <ref>PMID:19509286</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Lavrencic, P]]
+[[Category: Lavrencic P]]
-[[Category: Mobli, M]]
+[[Category: Mobli M]]
-[[Category: Immune system]]

2ndh

From Proteopedia

Current revision

NMR solution structure of MAL/TIRAP TIR domain (C116A)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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