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TitleStructure of the E3 ligase CRL2 with substrates reveals the molecular basis for N-degron recognition and ubiquitination.
Journal, issue, pagesCell Rep, Vol. 45, Issue 6, Page 117401, Year 2026
Publish dateJun 23, 2026
AuthorsXi Liu / Yang Li / Lennice K Castro / Zanlin Yu / Yifan Cheng / Matthew D Daugherty / John D Gross /
PubMed AbstractZYG11B is a substrate specificity factor for the cullin-2-RING ubiquitin ligase (CRL2), which plays a critical role in the recognition and degradation of Gly/N-degrons. Yet, how ZYG11B assembles with ...ZYG11B is a substrate specificity factor for the cullin-2-RING ubiquitin ligase (CRL2), which plays a critical role in the recognition and degradation of Gly/N-degrons. Yet, how ZYG11B assembles with CRL2, and how ZYG11B couples specific substrate recognition to CRL2-mediated ubiquitination, is unknown. We present the cryo-electron microscopy (cryo-EM) structures of the CRL2 holoenzyme alone and in complex with a Gly/N-peptide from the inflammasome-forming pathogen sensor NLRP1. The structures indicate that ZYG11B folds into a leucine-rich repeat followed by two armadillo repeat domains that promote assembly with CRL2 and specific recognition of the NLRP1 Gly/N-degron that is revealed by viral protease cleavage. Our structural and functional data indicate that blocking ZYG11B recognition of the NLRP1 Gly/N-degron inhibits NLRP1 inflammasome activation by a viral protease. Overall, we show how the CRL2 E3 ligase complex recognizes Gly/N-degron substrates, including those that are involved in viral protease-mediated activation of the NLRP1 inflammasome.
External linksCell Rep / PubMed:42224082 / PubMed Central
MethodsEM (single particle)
Resolution3.4 - 4.2 Å
Structure data

44588

9bid

EMDB-44588, PDB-9bid:
human ZYG11B and EloginB/C complex
Method: EM (single particle) / Resolution: 3.99 Å

44589

9bie

EMDB-44589, PDB-9bie:
human ZYG11B ElonginB/C complex binding to SARS-CoV2 Orf10 protein
Method: EM (single particle) / Resolution: 3.4 Å

44630

9bj8

EMDB-44630, PDB-9bj8:
human CRL2-ZYG11B complex
Method: EM (single particle) / Resolution: 3.78 Å

44631

9bj9

EMDB-44631, PDB-9bj9:
Human CRL-2 ZYG11B binding to human NLRP1 Gly/N degron
Method: EM (single particle) / Resolution: 4.2 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
  • severe acute respiratory syndrome coronavirus 2
KeywordsPEPTIDE BINDING PROTEIN / Gly/N degron / E3 ligase complex / peptide binding / Cullin E3 ligase

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