title: Structural and functional framework for the autoinhibition of Nedd4-family ubiquitin ligases.
abstract: Nedd4-family ubiquitin ligases are key regulators of cell surface receptor signaling. Their dysregulation is associated with several human diseases, including cancer. Under normal conditions, the activity of various Nedd4 E3s is controlled through an autoinhibitory interaction of the N-terminal C2 domain with the C-terminal catalytic HECT domain. Here, we report the structural and functional framework for this intramolecular interaction. Our nuclear magnetic resonance (NMR) data and biochemical analyses on Smurf2 and Nedd4 show that the C2 domain has the potential to regulate E3 activity by maintaining the HECT domain in a low-activity state where its ability for transthiolation and noncovalent Ub binding are impaired.
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Istituto Europeo di Oncologia, Via Adamello 16, Milan 20139, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Mari
authors.affiliation: Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ruetalo
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Istituto Europeo di Oncologia, Via Adamello 16, Milan 20139, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Maspero
authors.affiliation: Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
authors.forename: Mira C
authors.initials: MC
authors.lastname: Stoffregen
authors.affiliation: Crystallography Unit, Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Pasqualato
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Istituto Europeo di Oncologia, Via Adamello 16, Milan 20139, Italy; Dipartimento di Scienze della Salute, Universita' degli Studi di Milano, Via di Rudini 8, Milan 20122, Italy. Electronic address: simona.polo@ifom.eu.
authors.forename: Simona
authors.initials: S
authors.lastname: Polo
authors.affiliation: Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany. Electronic address: silke.wiesner@tue.mpg.de.
authors.forename: Silke
authors.initials: S
authors.lastname: Wiesner
mesh_terms: D020134:Catalytic Domain; D056827:Endosomal Sorting Complexes Required for Transport / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D000075702:Nedd4 Ubiquitin Protein Ligases; D017433:Protein Structure, Secondary; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases