title: The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation.
abstract: The DDB1-CUL4-RBX1 (CRL4) ubiquitin ligase family regulates a diverse set of cellular pathways through dedicated substrate receptors (DCAFs). The DCAF DDB2 detects UV-induced pyrimidine dimers in the genome and facilitates nucleotide excision repair. We provide the molecular basis for DDB2 receptor-mediated cyclobutane pyrimidine dimer recognition in chromatin. The structures of the fully assembled DDB1-DDB2-CUL4A/B-RBX1 (CRL4(DDB2)) ligases reveal that the mobility of the ligase arm creates a defined ubiquitination zone around the damage, which precludes direct ligase activation by DNA lesions. Instead, the COP9 signalosome (CSN) mediates the CRL4(DDB2) inhibition in a CSN5 independent, nonenzymatic, fashion. In turn, CSN inhibition is relieved upon DNA damage binding to the DDB2 module within CSN-CRL4(DDB2). The Cockayne syndrome A DCAF complex crystal structure shows that CRL4(DCAF(WD40)) ligases share common architectural features. Our data support a general mechanism of ligase activation, which is induced by CSN displacement from CRL4(DCAF) on substrate binding to the DCAF.
authors: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
authors: Eric S
authors: ES
authors: Fischer
authors: Andrea
authors: A
authors: Scrima
authors: Kerstin
authors: K
authors: Böhm
authors: Syota
authors: S
authors: Matsumoto
authors: Gondichatnahalli M
authors: GM
authors: Lingaraju
authors: Mahamadou
authors: M
authors: Faty
authors: Takeshi
authors: T
authors: Yasuda
authors: Simone
authors: S
authors: Cavadini
authors: Mitsuo
authors: M
authors: Wakasugi
authors: Fumio
authors: F
authors: Hanaoka
authors: Shigenori
authors: S
authors: Iwai
authors: Heinz
authors: H
authors: Gut
authors: Kaoru
authors: K
authors: Sugasawa
authors: Nicolas H
authors: NH
authors: Thomä
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D044842:Cullin Proteins / Q000737:chemistry; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism; D051760:Xeroderma Pigmentosum Group A Protein / Q000737:chemistry
chemical_list: C114234:CUL4A protein, human; D044842:Cullin Proteins; C091435:DDB1 protein, human; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D051760:Xeroderma Pigmentosum Group A Protein; D044767:Ubiquitin-Protein Ligases