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Uncovering the Mechanism of Forkhead-Associated Domain-Mediated TIFA Oligomerization That Plays a Central Role in Immune Responses.
Weng, Jui-Hung; Hsieh, Yin-Cheng; Huang, Chia-Chi Flora; Wei, Tong-You Wade; Lim, Liang-Hin; Chen, Yu-Hou; Ho, Meng-Ru; Wang, Iren; Huang, Kai-Fa; Chen, Chun-Jung; Tsai, Ming-Daw.
Afiliación
  • Weng JH; Institute of Biological Chemistry, Academia Sinica , Taipei, Taiwan.
  • Hsieh YC; Taiwan International Graduate Program, Academia Sinica , Taipei, Taiwan.
  • Huang CC; Institute of Biochemical Sciences, Department of Chemistry, National Tsing Hua University , Hsinchu, Taiwan.
  • Wei TY; Life Science Group, Scientific Research Division, National Synchrotron Radiation Research Center , Hsinchu, Taiwan.
  • Lim LH; Institute of Biological Chemistry, Academia Sinica , Taipei, Taiwan.
  • Chen YH; Taiwan International Graduate Program, Academia Sinica , Taipei, Taiwan.
  • Ho MR; Institute of Biochemical Sciences, National Taiwan University , Taipei, Taiwan.
  • Wang I; Institute of Biological Chemistry, Academia Sinica , Taipei, Taiwan.
  • Huang KF; Institute of Biochemical Sciences, National Taiwan University , Taipei, Taiwan.
  • Chen CJ; Institute of Biological Chemistry, Academia Sinica , Taipei, Taiwan.
  • Tsai MD; Institute of Biochemical Sciences, National Taiwan University , Taipei, Taiwan.
Biochemistry ; 54(40): 6219-29, 2015 Oct 13.
Article en En | MEDLINE | ID: mdl-26389808
Forkhead-associated (FHA) domain is the only signaling domain that recognizes phosphothreonine (pThr) specifically. TRAF-interacting protein with an FHA domain (TIFA) was shown to be involved in immune responses by binding with TRAF2 and TRAF6. We recently reported that TIFA is a dimer in solution and that, upon stimulation by TNF-α, TIFA is phosphorylated at Thr9, which triggers TIFA oligomerization via pThr9-FHA domain binding and activates nuclear factor κB (NF-κB). However, the structural mechanism for the functionally important TIFA oligomerization remains to be established. While FHA domain-pThr binding is known to mediate protein dimerization, its role in oligomerization has not been demonstrated at the structural level. Here we report the crystal structures of TIFA (residues 1-150, with the unstructured C-terminal tail truncated) and its complex with the N-terminal pThr9 peptide (residues 1-15), which show unique features in the FHA structure (intrinsic dimer and extra ß-strand) and in its interaction with the pThr peptide (with residues preceding rather than following pThr). These structural features support previous and additional functional analyses. Furthermore, the structure of the complex suggests that the pThr9-FHA domain interaction can occur only between different sets of dimers rather than between the two protomers within a dimer, providing the structural mechanism for TIFA oligomerization. Our results uncover the mechanism of FHA domain-mediated oligomerization in a key step of immune responses and expand the paradigm of FHA domain structure and function.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Fosfotreonina / Proteínas Adaptadoras Transductoras de Señales Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Biochemistry Año: 2015 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Fosfotreonina / Proteínas Adaptadoras Transductoras de Señales Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Biochemistry Año: 2015 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Estados Unidos