Structural basis for TIR domain-mediated innate immune signaling by Toll- like receptor adaptors TRIF and TRAM

• 成果类型: Article
• 署名作者: Manik, Mohammad K.; Pan, Mengqi; Xiao, Le; Gu, Weixi; Kim, Hyoyoung; Pospich, Sabrina; Hedger, Andrew; Vajjhala, Parimala R.; Lee, Morris Y. L.; Qian, Xiaoqi; Landsberg, Michael J.; Ve, Thomas; Nanson, Jeffrey D.; Raunser, Stefan; Stacey, Katryn J.; Wu, Hao; Kobe, Bostjan
• 署名单位: Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Program in Cellular & Molecular Medicine (PCMM); University of Queensland; University of Queensland; University of Queensland; Max Planck Society; Griffith University; Griffith University - Gold Coast Campus; Charles Sturt University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11084
• DOI: 10.1073/pnas.2418988122
• 发表日期: 2025-01-14
• 关键词: nf-kappa-b; assembly formation; molecule; complex; toll-like-receptor-4; mechanisms; ticam-1; tlr4; form

摘要

Innate immunity relies on Toll- like receptors (TLRs) to detect pathogen- associated molecadaptor molecule) are essential for MyD88- independent TLR signaling. However, the structural basis of TRIF and TRAM TIR domain-based signaling remains unclear. Here, we present cryo- EM structures of filaments formed by TRIF and TRAM TIR domains at resolutions of 3.3 & Aring; and 5.6 & Aring;, respectively. Both structures reveal two- stranded parallel helical arrangements. Functional studies underscore the importance of intrastrand interactions, mediated by the BB- loop, and interstrand interactions in TLR4- mediated signaling. inactivity. Our findings suggest a unified signaling mechanism by the TIR domains of therapeutic targets for immunity- related disorders.