title: Structural Insights into mitochondrial antiviral signaling protein (MAVS)-tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling.
abstract: In response to viral infection, cytosolic retinoic acid-inducible gene I-like receptors sense viral RNA and promote oligomerization of mitochondrial antiviral signaling protein (MAVS), which then recruits tumor necrosis factor receptor-associated factor (TRAF) family proteins, including TRAF6, to activate an antiviral response. Currently, the interaction between MAVS and TRAF6 is only partially understood, and atomic details are lacking. Here, we demonstrated that MAVS directly interacts with TRAF6 through its potential TRAF6-binding motif 2 (T6BM2; amino acids 455-460). Further, we solved the crystal structure of MAVS T6BM2 in complex with the TRAF6 TRAF_C domain at 2.95 Å resolution. T6BM2 of MAVS binds to the canonical adaptor-binding groove of the TRAF_C domain. Structure-directed mutational analyses in vitro and in cells revealed that MAVS binding to TRAF6 via T6BM2 instead of T6BM1 is essential but not sufficient for an optimal antiviral response. Particularly, a MAVS mutant Y460E retained its TRAF6-binding ability as predicted but showed significantly impaired signaling activity, highlighting the functional importance of this tyrosine. Moreover, these observations were further confirmed in MAVS(-/-) mouse embryonic fibroblast cells. Collectively, our work provides a structural basis for understanding the MAVS-TRAF6 antiviral response.
authors.affiliation: From the School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China, the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, State Key Laboratory of Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China, and.
authors.forename: Zhubing
authors.initials: Z
authors.lastname: Shi
authors.affiliation: the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, State Key Laboratory of Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China, and.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, State Key Laboratory of Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China, and.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, State Key Laboratory of Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China, and.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, State Key Laboratory of Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China, and.
authors.forename: Chuanchuan
authors.initials: C
authors.lastname: Li
authors.affiliation: the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, State Key Laboratory of Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China, and.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, State Key Laboratory of Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China, and.
authors.forename: Feng
authors.initials: F
authors.lastname: He
authors.affiliation: Qingdao Binhai University, Qingdao, Shandong 266555, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Sun
authors.affiliation: the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, State Key Laboratory of Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China, and.
authors.forename: Shi
authors.initials: S
authors.lastname: Jiao
authors.affiliation: From the School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China, wshi@tongji.edu.cn.
authors.forename: Weiyang
authors.initials: W
authors.lastname: Shi
authors.affiliation: the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, State Key Laboratory of Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China, and zczhou@sibcb.ac.cn.
authors.forename: Zhaocai
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000821:virology; D015870:Gene Expression; D017930:Genes, Reporter; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000821:virology; D008969:Molecular Sequence Data; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D029082:Sendai virus / Q000502:physiology; D016415:Sequence Alignment; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D011993:Recombinant Fusion Proteins; D048029:TNF Receptor-Associated Factor 6; D008156:Luciferases
keywords: Antiviral signaling; MAVS; TNF receptor associated factor (TRAF); TRAF6; crystal structure; innate immunity; protein-protein interaction; signal transduction