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  • Ectodomain of the toll-like receptor 4 prevents constitutive receptor activation [Elektronski vir]
    Panter, Gabriela ; Jerala, Roman
    Toll-like receptor 4 (TLR4) is involved in activation of innate immune response in a large number of different diseases. Despite numerous studies, the role of separate domains of TLR4 in the ... regulation of receptor activation is poorly understood. Replacement of the TLR4 ectodomain with LPS-binding proteins MD-2 or CD14 resulted in a robust ligand-independent constitutive activation, comparable to the maximal stimulation of the receptor with LPS. The same effect was achieved by the replacement of the ectodomain with a monomeric fluorescent protein or a 24 kDa gyrase B fragment. This demonstratesan intrinsic dimerization propensity of the transmembrane and cytoplasmic domains of TLR4 and reveals a previously unknown function of the ectodomain in inhibiting spontaneous receptor dimerization. Constitutive activation was abolished by the replacement of ectodomain by a bulkier proteinovalbumin. N-terminal deletion variants of TLR4 revealed that the smallest segment of the ectodomain that already prevents constitutive activitycomprises only 90 residues (542 to 631) out of the total 608 residues.We conclude that TLR4 represents a receptor with low threshold of activation, which can be rapidly activated by the release of inhibition exerted by its ectodomain. This is important for the sensitivity of TLR4 to activation by different agonists. TLR4 ectodomain has multiple roles in enabling ligand regulated activation, providing proper localization, while serving as an inhibitor to prevent spontaneous, ligand-independent dimerization.
    Source: Journal of biological chemistry [Elektronski vir]. - ISSN 1083-351X (Vol. 286, no. 26, 2011, str. 23334-23344)
    Type of material - e-article
    Publish date - 2011
    Language - english
    COBISS.SI-ID - 4652570
    DOI

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