title: Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome.
abstract: The cullin-RING ubiquitin E3 ligase (CRL) family comprises over 200 members in humans. The COP9 signalosome complex (CSN) regulates CRLs by removing their ubiquitin-like activator NEDD8. The CUL4A-RBX1-DDB1-DDB2 complex (CRL4A(DDB2)) monitors the genome for ultraviolet-light-induced DNA damage. CRL4A(DBB2) is inactive in the absence of damaged DNA and requires CSN to regulate the repair process. The structural basis of CSN binding to CRL4A(DDB2) and the principles of CSN activation are poorly understood. Here we present cryo-electron microscopy structures for CSN in complex with neddylated CRL4A ligases to 6.4 Å resolution. The CSN conformers defined by cryo-electron microscopy and a novel apo-CSN crystal structure indicate an induced-fit mechanism that drives CSN activation by neddylated CRLs. We find that CSN and a substrate cannot bind simultaneously to CRL4A, favouring a deneddylated, inactive state for substrate-free CRL4 complexes. These architectural and regulatory principles appear conserved across CRL families, allowing global regulation by CSN.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.|University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Cavadini
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.|University of Basel, Petersplatz 10, 4003 Basel, Switzerland.|Department of Cancer Biology, Dana-Farber Cancer Institute, LC-4312, 360 Longwood Avenue, Boston, Massachusetts 02215, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Fischer
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.|University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bunker
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.|University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Potenza
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.|University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
authors.forename: Gondichatnahalli M
authors.initials: GM
authors.lastname: Lingaraju
authors.affiliation: Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, 4058 Basel, Switzerland.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Goldie
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.|University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
authors.forename: Weaam I
authors.initials: WI
authors.lastname: Mohamed
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.|University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Faty
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.|University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Petzold
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Rohan E J
authors.initials: RE
authors.lastname: Beckwith
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Ritesh B
authors.initials: RB
authors.lastname: Tichkule
authors.affiliation: Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hassiepen
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.|University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
authors.forename: Wassim
authors.initials: W
authors.lastname: Abdulrahman
authors.affiliation: Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, 4058 Basel, Switzerland.|Gatan R&D, 5974 W. Las Positas Boulevard, Pleasanton, California 94588, USA.
authors.forename: Radosav S
authors.initials: RS
authors.lastname: Pantelic
authors.affiliation: Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Kobe 657-8501, Japan.|Graduate School of Science, Kobe University, Kobe, 657-8501, Japan.
authors.forename: Syota
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Kobe 657-8501, Japan.|Graduate School of Science, Kobe University, Kobe, 657-8501, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sugasawa
authors.affiliation: Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, 4058 Basel, Switzerland.
authors.forename: Henning
authors.initials: H
authors.lastname: Stahlberg
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.|University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
authors.forename: Nicolas H
authors.initials: NH
authors.lastname: Thomä
mesh_terms: D000494:Allosteric Regulation; D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D001665:Binding Sites; D055162:Biocatalysis; D000075686:COP9 Signalosome Complex; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D044842:Cullin Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D011485:Protein Binding; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D001059:Apoproteins; C114234:CUL4A protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C091435:DDB1 protein, human; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; C479529:RBX1 protein, human; D014452:Ubiquitins; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex