title: Structures of SMG1-UPFs complexes: SMG1 contributes to regulate UPF2-dependent activation of UPF1 in NMD.
abstract: SMG1, a PI3K-related kinase, plays a critical role in nonsense-mediated mRNA decay (NMD) in mammals. SMG1-mediated phosphorylation of the UPF1 helicase is an essential step during NMD initiation. Both SMG1 and UPF1 are presumably activated by UPF2, but this regulation is incompletely understood. Here we reveal that SMG1C (a complex containing SMG1, SMG8, and SMG9) contributes to regulate NMD by recruiting UPF1 and UPF2 to distinct sites in the vicinity of the kinase domain. UPF2 binds SMG1 in an UPF1-independent manner in vivo, and the SMG1C-UPF2 structure shows UPF2 recognizes the FRB domain, a region that regulates the related mTOR kinase. The molecular architectures of several SMG1C-UPFs complexes, obtained by combining electron microscopy with in vivo and in vitro interaction analyses, competition experiments, and mutations, suggest that UPF2 can be transferred to UPF1 within SMG1C, inducing UPF2-dependent conformational changes required to activate UPF1 within an SMG1C-UPF1-UPF2 complex.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (Spanish National Research Council), Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Melero
authors.affiliation: Department of Molecular Biology, Yokohama City University School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Uchiyama
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (Spanish National Research Council), Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Castaño
authors.affiliation: Medical Innovation Center, Laboratory for Malignancy Control Research, Kyoto University Graduate School of Medicine, 53, Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kataoka
authors.affiliation: Department of Molecular Biology, Yokohama City University School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Kurosawa
authors.affiliation: Department of Molecular Biology, Yokohama City University School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Molecular Biology, Yokohama City University School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. Electronic address: yamasita@yokohama-cu.ac.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Yamashita
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (Spanish National Research Council), Ramiro de Maeztu 9, 28040 Madrid, Spain. Electronic address: ollorca@cib.csic.es.
authors.forename: Oscar
authors.initials: O
authors.lastname: Llorca
mesh_terms: D015153:Blotting, Western; D004789:Enzyme Activation / Q000502:physiology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008854:Microscopy, Electron; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases; D020365:RNA Helicases; D016601:RNA-Binding Proteins; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D020365:RNA Helicases; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C468286:UPF2 protein, human; C514704:SMG1 protein, human; C101828:UPF1 protein, human