title: The Brucella TIR-like protein TcpB interacts with the death domain of MyD88.
abstract: The pathogen Brucella melitensis secretes a Toll/interleukin-1 receptor (TIR) domain containing protein that abrogates host innate immune responses. In this study, we have characterized the biochemical interactions of Brucella TIR-like protein TcpB with host innate immune adaptor proteins. Using protein-fragment complementation assays based on Gaussia luciferase and green fluorescent protein, we find that TcpB interacts directly with MyD88 and that this interaction is significantly stronger than the interaction of TcpB with TIRAP, the only other adaptor protein that detectably interacts with TcpB. Surprisingly, the TcpB-MyD88 interaction depends on the death domain (DD) of MyD88, and TcpB does not interact with the isolated TIR domain of MyD88. TcpB disrupts MyD88(DD)-MyD88(DD), MyD88(DD)-MyD88(TIR) and MyD88(DD)-MyD88 interactions but not MyD88-MyD88 or MyD88(TIR)-MyD88(TIR) interactions. Structural models consistent with these results suggest how TcpB might inhibit TLR signaling by targeting MyD88 via a DD-TIR domain interface.
authors.affiliation: Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA. anuc@u.washington.edu
authors.forename: Anu
authors.initials: A
authors.lastname: Chaudhary
authors.forename: Kumkum
authors.initials: K
authors.lastname: Ganguly
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Cabantous
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Waldo
authors.forename: Sofiya N
authors.initials: SN
authors.lastname: Micheva-Viteva
authors.forename: Kamalika
authors.initials: K
authors.lastname: Nag
authors.forename: William S
authors.initials: WS
authors.lastname: Hlavacek
authors.forename: Chang-Shung
authors.initials: CS
authors.lastname: Tung
mesh_terms: D000818:Animals; D017347:Brucella melitensis / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D049452:Green Fluorescent Proteins / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D008156:Luciferases / Q000737:chemistry; D053594:Myeloid Differentiation Factor 88 / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D049452:Green Fluorescent Proteins; D008156:Luciferases