title: Model of the Ankyrin and SOCS Box Protein, ASB9, E3 Ligase Reveals a Mechanism for Dynamic Ubiquitin Transfer.
abstract: Cullin-RING E3 ligases (CRLs) are elongated and bowed protein complexes that transfer ubiquitin over 60 Å to proteins targeted for proteasome degradation. One such CRL contains the ankyrin repeat and SOCS box protein 9 (ASB9), which binds to and partially inhibits creatine kinase (CK). While current models for the ASB9-CK complex contain some known interface residues, the overall structure and precise interface of the ASB9-CK complex remains unknown. Through an integrative modeling approach, we report a third-generation model that reveals precisely the interface interactions and also fits the shape of the ASB9-CK complex as determined by small-angle X-ray scattering. We constructed an atomic model for the entire CK-targeting CRL to uncover dominant modes of motion that could permit ubiquitin transfer. Remarkably, only the correctly docked CK-containing E3 ligase and not incorrectly docked structures permitted close approach of ubiquitin to the CK substrate.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0378, USA.
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Schiffer
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0378, USA; National Biomedical Computation Resource, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0608, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Malmstrom
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0378, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Parnell
authors.affiliation: Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Casilla 653, Santiago 7800003, Chile.
authors.forename: Cesar
authors.initials: C
authors.lastname: Ramirez-Sarmiento
authors.affiliation: Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Casilla 653, Santiago 7800003, Chile.
authors.forename: Javiera
authors.initials: J
authors.lastname: Reyes
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0378, USA; National Biomedical Computation Resource, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0608, USA. Electronic address: ramaro@ucsd.edu.
authors.forename: Rommie E
authors.initials: RE
authors.lastname: Amaro
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0378, USA. Electronic address: ekomives@ucsd.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Komives
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D003001:Cloning, Molecular; D003402:Creatine Kinase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053838:Scattering, Small Angle; D013379:Substrate Specificity; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D025801:Ubiquitin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D014961:X-Ray Diffraction
chemical_list: C540562:ASB9 protein, human; D011994:Recombinant Proteins; D050826:Suppressor of Cytokine Signaling Proteins; D025801:Ubiquitin; D003402:Creatine Kinase