Biochem Biophys Res Commun. 2009 Feb 27;380(1):183-7. Epub 2009 Jan 22.

Contribution of globular death domains and unstructured linkers to MyD88.IRAK-4 heterodimer formation: an explanation for the antagonistic activity of MyD88s.External

Mendoza-Barbera, E., Corral-Rodriguez, M. A., Soares-Schanoski, A., Velarde, M., Macieira, S., Messerschmidt, A., Lopez-Collazo, E., Fuentes-Prior, P.,
--- - Cardiovascular Research Center and Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
Homotypic interactions of death domains (DD) mediate complex formation between MyD88 and IL-1 receptor-associated kinases (IRAKs). A truncated splice variant of MyD88, MyD88s, cannot recruit IRAK-4 and fails to elicit inflammatory responses. We have generated recombinant DD of MyD88 and IRAK-4, both alone and extended by the linkers to TIR or kinase domains. We show that both MyD88 DD variants bind to the linker-extended IRAK-4 DD and pull-down full-length IRAK-4 from monocyte extracts. By contrast, residues up to Glu(116) from the DD-kinase connector of IRAK-4 are needed for strong interactions with the adaptor. Our findings indicate that residues 110-120, which form a C-terminal extra helix in MyD88, but not the irregular linker between DD and TIR domains, are required for IRAK-4 recruitment, and provide a straightforward explanation for the negative regulation of innate immune responses mediated by MyD88s.
PMID: 19167362External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vitro interaction
  DD1 DD2 Reference
Family DD1 DD2 Method Species Region Expression Species Region Expression
DD IRAK4 Link Myd88 His fusion protein pull-down Human 1-185 E.coli Human 1-157 E.coli 19167362
(Link: click this icon to show interactions only between the two corresponding DDs)