5nao

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NMR structure of TLR4 transmembrane domain (624-657) in DPC micelles

Structural highlights

5nao 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

Disease

TLR4_HUMAN Genetic variation in TLR4 is associated with age-related macular degeneration type 10 (ARMD10) [MIM:611488. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.

Function

TLR4_HUMAN Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Also involved in LPS-independent inflammatory responses triggered by Ni(2+). These responses require non-conserved histidines and are, therefore, species-specific.[1]

Publication Abstract from PubMed

Toll-like receptors (TLRs) play a key role in the innate and adaptive immune systems. While a lot of structural data is available for the extracellular and cytoplasmic domains of TLRs, and a model of the dimeric full-length TLR3 receptor in the active state was build, the conformation of the transmembrane (TM) domain and juxtamembrane regions in TLR dimers is still unclear. In the present work, we study the transmembrane and juxtamembrane parts of human TLR4 receptor using solution NMR spectroscopy in a variety of membrane mimetics, including phospholipid bicelles. We show that the juxtamembrane hydrophobic region of TLR4 includes a part of long TM alpha-helix. We report the dimerization interface of the TM domain and claim that long TM domains with transmembrane charged aminoacids is a common feature of human toll-like receptors. This fact is analyzed from the viewpoint of protein activation mechanism, and a model of full-length TLR4 receptor in the dimeric state has been proposed.

Spatial structure of TLR4 transmembrane domain in bicelles provides the insight into the receptor activation mechanism.,Mineev KS, Goncharuk SA, Goncharuk MV, Volynsky PE, Novikova EV, Aresinev AS Sci Rep. 2017 Jul 31;7(1):6864. doi: 10.1038/s41598-017-07250-4. PMID:28761155[2]

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

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Citations
2 reviews cite this structure
A Structural Perspective on Calprotectin as a Ligand of Receptors Mediating Inflammation and Potential Drug Target.
Garcia et al. (2022)
1 more
8 other articles
No citations found

See Also

References

  1. ↑ Schmidt M, Raghavan B, Muller V, Vogl T, Fejer G, Tchaptchet S, Keck S, Kalis C, Nielsen PJ, Galanos C, Roth J, Skerra A, Martin SF, Freudenberg MA, Goebeler M. Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol. 2010 Sep;11(9):814-9. doi: 10.1038/ni.1919. Epub 2010 Aug 15. PMID:20711192 doi:10.1038/ni.1919
  2. ↑ Mineev KS, Goncharuk SA, Goncharuk MV, Volynsky PE, Novikova EV, Aresinev AS. Spatial structure of TLR4 transmembrane domain in bicelles provides the insight into the receptor activation mechanism. Sci Rep. 2017 Jul 31;7(1):6864. doi: 10.1038/s41598-017-07250-4. PMID:28761155 doi:http://dx.doi.org/10.1038/s41598-017-07250-4

Contents


PDB ID 5nao

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