The Amino-terminal Region of Toll-like Receptor 4 Is Essential for Binding to MD-2 and Receptor Translocation to the Cell Surface
Toll-like receptor 4 (TLR4) and MD-2 are pivotal components that elicit inflammatory responses to lipopolysaccharide (LPS). They have been shown to form a physical complex on the cell surface that responds directly to LPS. However, the functional region of TLR4 required for association with MD-2 and...
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Veröffentlicht in: | The Journal of biological chemistry 2004-11, Vol.279 (46), p.47431-47437 |
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Sprache: | eng |
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Zusammenfassung: | Toll-like receptor 4 (TLR4) and MD-2 are pivotal components that elicit inflammatory responses to lipopolysaccharide (LPS).
They have been shown to form a physical complex on the cell surface that responds directly to LPS. However, the functional
region of TLR4 required for association with MD-2 and LPS responsiveness is poorly understood. To identify the region of TLR4,
we created a series of mutants with deletions in the extracellular domain and examined their activities in human embryonic
kidney 293 cells. A mutant with a 317-amino acid deletion from the membrane proximal region of TLR4 was capable of associating
with MD-2, while only a 9-amino acid truncation of the N terminus severely impaired the interaction. The association between
the two molecules was well correlated with TLR4 maturation into an endoglycosidase H-resistant form and the cell surface expression.
Mouse MD-2 bound to human TLR4, but its activity to facilitate the cell surface expression of TLR4 and confer LPS responsiveness
was much weaker than that of human MD-2, indicating species specificity. A chimeric receptor composed of the N-terminal region
of human TLR4 and the adjacent region of mouse TLR4 showed preference for human MD-2 in its transport to the cell surface
and responsiveness to LPS. Taken together, the N-terminal region of TLR4 is essential for association with MD-2, which is
required for the cell surface expression and hence the responsiveness to LPS. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M408724200 |