title: Contribution of globular death domains and unstructured linkers to MyD88.IRAK-4 heterodimer formation: an explanation for the antagonistic activity of MyD88s.
abstract: 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.
authors.affiliation: Cardiovascular Research Center and Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Mendoza-Barberá
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Corral-Rodríguez
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soares-Schanoski
authors.forename: Milko
authors.initials: M
authors.lastname: Velarde
authors.forename: Sofia
authors.initials: S
authors.lastname: Macieira
authors.forename: Albrecht
authors.initials: A
authors.lastname: Messerschmidt
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Collazo
authors.forename: Pablo
authors.initials: P
authors.lastname: Fuentes-Prior
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019281:Dimerization; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008956:Models, Chemical; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D011994:Recombinant Proteins; D018698:Glutamic Acid; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases