Contribution of globular death domains and unstructured linkers to MyD88(.)IRAK-4 heterodimer formation: An explanation for the antagonistic activity of MyD88s
Por:
Mendoza-Barbera, E, Corral-Rodriguez, MA, Soares-Schanoski, A, Velarde, M, Macieira, S, Messerschmidt, A, Lopez-Collazo, E, Fuentes-Prior, P
Publicada:
27 feb 2009
Resumen:
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. (C) 2009 Elsevier Inc. All rights reserved
Filiaciones:
Mendoza-Barbera, E:
Hosp Santa Creu & Sant Pau, Ctr Cardiovasc, E-08025 Barcelona, Spain
Hosp Santa Creu & Sant Pau, Inst Recerca, E-08025 Barcelona, Spain
Hosp La Paz, Lab Tumor Immunol, Res Unit, Madrid 28046, Spain
Corral-Rodriguez, MA:
Hosp Santa Creu & Sant Pau, Ctr Cardiovasc, E-08025 Barcelona, Spain
Hosp Santa Creu & Sant Pau, Inst Recerca, E-08025 Barcelona, Spain
Soares-Schanoski, A:
Hosp La Paz, Lab Tumor Immunol, Res Unit, Madrid 28046, Spain
Velarde, M:
Max Planck Inst Biochem, D-82152 Munich, Germany
Macieira, S:
Max Planck Inst Biochem, D-82152 Munich, Germany
Messerschmidt, A:
Max Planck Inst Biochem, D-82152 Munich, Germany
Lopez-Collazo, E:
Hosp La Paz, Lab Tumor Immunol, Res Unit, Madrid 28046, Spain
Fuentes-Prior, P:
Hosp Santa Creu & Sant Pau, Ctr Cardiovasc, E-08025 Barcelona, Spain
Hosp Santa Creu & Sant Pau, Inst Recerca, E-08025 Barcelona, Spain
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