ISG15 activating enzyme activity / ISG15 transferase activity / 合成酵素; C-S結合を形成; 酸とチオールを結合するもの / positive regulation of protein oligomerization / ISG15-protein conjugation / regulation of type II interferon production / protein localization to mitochondrion / NS1 Mediated Effects on Host Pathways / response to type I interferon / negative regulation of type I interferon-mediated signaling pathway ...ISG15 activating enzyme activity / ISG15 transferase activity / 合成酵素; C-S結合を形成; 酸とチオールを結合するもの / positive regulation of protein oligomerization / ISG15-protein conjugation / regulation of type II interferon production / protein localization to mitochondrion / NS1 Mediated Effects on Host Pathways / response to type I interferon / negative regulation of type I interferon-mediated signaling pathway / E2 ubiquitin-conjugating enzyme / negative regulation of viral genome replication / RSV-host interactions / ubiquitin conjugating enzyme activity / positive regulation of interleukin-10 production / polyubiquitin modification-dependent protein binding / positive regulation of bone mineralization / ubiquitin ligase complex / negative regulation of protein ubiquitination / positive regulation of interferon-beta production / positive regulation of erythrocyte differentiation / ubiquitin binding / Negative regulators of DDX58/IFIH1 signaling / integrin-mediated signaling pathway / Termination of translesion DNA synthesis / DDX58/IFIH1-mediated induction of interferon-alpha/beta / response to virus / protein modification process / PKR-mediated signaling / ISG15 antiviral mechanism / modification-dependent protein catabolic process / protein polyubiquitination / protein tag activity / ubiquitin-protein transferase activity / Interferon alpha/beta signaling / positive regulation of type II interferon production / Antigen processing: Ubiquitination & Proteasome degradation / integrin binding / ubiquitin-dependent protein catabolic process / defense response to virus / protein ubiquitination / defense response to bacterium / Amyloid fiber formation / innate immune response / ubiquitin protein ligase binding / DNA damage response / SARS-CoV-2 activates/modulates innate and adaptive immune responses / extracellular region / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol 類似検索 - 分子機能
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
米国
引用
ジャーナル: Nat Commun / 年: 2023 タイトル: Cryo-EM structures of Uba7 reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer. 著者: Mohammad Afsar / GuanQun Liu / Lijia Jia / Eliza A Ruben / Digant Nayak / Zuberwasim Sayyad / Priscila Dos Santos Bury / Kristin E Cano / Anindita Nayak / Xiang Ru Zhao / Ankita Shukla / ...著者: Mohammad Afsar / GuanQun Liu / Lijia Jia / Eliza A Ruben / Digant Nayak / Zuberwasim Sayyad / Priscila Dos Santos Bury / Kristin E Cano / Anindita Nayak / Xiang Ru Zhao / Ankita Shukla / Patrick Sung / Elizabeth V Wasmuth / Michaela U Gack / Shaun K Olsen / 要旨: ISG15 plays a crucial role in the innate immune response and has been well-studied due to its antiviral activity and regulation of signal transduction, apoptosis, and autophagy. ISG15 is a ubiquitin- ...ISG15 plays a crucial role in the innate immune response and has been well-studied due to its antiviral activity and regulation of signal transduction, apoptosis, and autophagy. ISG15 is a ubiquitin-like protein that is activated by an E1 enzyme (Uba7) and transferred to a cognate E2 enzyme (UBE2L6) to form a UBE2L6-ISG15 intermediate that functions with E3 ligases that catalyze conjugation of ISG15 to target proteins. Despite its biological importance, the molecular basis by which Uba7 catalyzes ISG15 activation and transfer to UBE2L6 is unknown as there is no available structure of Uba7. Here, we present cryo-EM structures of human Uba7 in complex with UBE2L6, ISG15 adenylate, and ISG15 thioester intermediate that are poised for catalysis of Uba7-UBE2L6-ISG15 thioester transfer. Our structures reveal a unique overall architecture of the complex compared to structures from the ubiquitin conjugation pathway, particularly with respect to the location of ISG15 thioester intermediate. Our structures also illuminate the molecular basis for Uba7 activities and for its exquisite specificity for ISG15 and UBE2L6. Altogether, our structural, biochemical, and human cell-based data provide significant insights into the functions of Uba7, UBE2L6, and ISG15 in cells.