7ZN7

Cryo-EM structure of RCMV-E E27 bound to human DDB1 (deltaBPB) and rat STAT2 CCD

Summary for 7ZN7

• Entry DOI: 10.2210/pdb7zn7/pdb
• EMDB information: 14802
• Descriptor: DNA damage-binding protein 1, B27a, Signal transducer and activator of transcription, ... (4 entities in total)
• Functional Keywords: interferon, ubiquitin-proteasome system, cullin-ring ubiquitin ligases (crl), ddb1, dcafs, viral dcaf (vdcaf), cytomegalovirus, stat2, irf9, virus
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 267251.72

Authors

Lauer, S.,Spahn, C.M.T.,Schwefel, D. (deposition date: 2022-04-20, release date: 2022-11-09, Last modification date: 2024-07-24)

Primary citation

Le-Trilling, V.T.K.,Banchenko, S.,Paydar, D.,Leipe, P.M.,Binting, L.,Lauer, S.,Graziadei, A.,Klingen, R.,Gotthold, C.,Burger, J.,Bracht, T.,Sitek, B.,Jan Lebbink, R.,Malyshkina, A.,Mielke, T.,Rappsilber, J.,Spahn, C.M.,Voigt, S.,Trilling, M.,Schwefel, D.
Structural mechanism of CRL4-instructed STAT2 degradation via a novel cytomegaloviral DCAF receptor.
Embo J., 42:e112351-e112351, 2023

PubMed Abstract: Human cytomegalovirus (CMV) is a ubiquitously distributed pathogen whose rodent counterparts such as mouse and rat CMV serve as common infection models. Here, we conducted global proteome profiling of rat CMV-infected cells and uncovered a pronounced loss of the transcription factor STAT2, which is crucial for antiviral interferon signalling. Via deletion mutagenesis, we found that the viral protein E27 is required for CMV-induced STAT2 depletion. Cellular and in vitro analyses showed that E27 exploits host-cell Cullin4-RING ubiquitin ligase (CRL4) complexes to induce poly-ubiquitylation and proteasomal degradation of STAT2. Cryo-electron microscopy revealed how E27 mimics molecular surface properties of cellular CRL4 substrate receptors called DCAFs (DDB1- and Cullin4-associated factors), thereby displacing them from the catalytic core of CRL4. Moreover, structural analyses showed that E27 recruits STAT2 through a bipartite binding interface, which partially overlaps with the IRF9 binding site. Structure-based mutations in M27, the murine CMV homologue of E27, impair the interferon-suppressing capacity and virus replication in mouse models, supporting the conserved importance of DCAF mimicry for CMV immune evasion.

PubMed: 36762436
DOI: 10.15252/embj.2022112351

Experimental method

ELECTRON MICROSCOPY (3.78 Å)