ArticleProceedings of the National Academy of Sciences of the United States of America2017
Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- o-Vanillin binds covalently to MAL/TIRAP Lys-210 but independently inhibits TLR2.Journal of enzyme inhibition and medicinal chemistry · 2024Article
- Review
- Human and Bacterial Toll-Interleukin Receptor Domains Exhibit Distinct Dynamic Features and Functions.Molecules (Basel, Switzerland) · 2022Article
- Modulation of Toll-like receptor 1 intracellular domain structure and activity by ZnCommunications biology · 2021Article
- Redox regulation of immunity and the role of small molecular weight thiols.Redox biology · 2021Article
- TLRs in Mycobacterial Pathogenesis: Black and White or Shades of Gray.Current microbiology · 2021Review
- Mechanics of a molecular mousetrap-nucleation-limited innate immune signaling.Biophysical journal · 2021Review
- TIRAP in the Mechanism of Inflammation.Frontiers in immunology · 2021Review
- Absence of Mal/TIRAP Results in Abrogated Imidazoquinolinones-Dependent Activation of IRF7 and Suppressed IFNβ and IFN-I Activated Gene Production.International journal of molecular sciences · 2020Article
- Endoplasmic reticulum stress and glutathione therapeutics in chronic lung diseases.Redox biology · 2020Review
- A Computational Probe into the Structure and Dynamics of the Full-Length Toll-Like Receptor 3 in a Phospholipid Bilayer.International journal of molecular sciences · 2020Article
- A survey of TIR domain sequence and structure divergence.Immunogenetics · 2020Article
- Dysregulation of the glutaredoxin/American journal of physiology. Cell physiology · 2020Article
- A peptide derived from the core β-sheet region of TIRAP decoys TLR4 and reduces inflammatory and autoimmune symptoms in murine models.EBioMedicine · 2020Article
- Paradoxical Roles of the MAL/Tirap Adaptor in Pathologies.Frontiers in immunology · 2020Review
- Targeting the TLR signalosome with TIR domain-derived cell-permeable decoy peptides: the current state and perspectives.Innate immunity · 2020Review
- Select targeting of intracellular Toll-interleukin-1 receptor resistance domains for protection against influenza-induced disease.Innate immunity · 2020Article
- Toll-like receptor 4: A promising therapeutic target for pneumonia caused by Gram-negative bacteria.Journal of cellular and molecular medicine · 2019Review
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12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 β-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.
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