Structure of UBE2K-Ub/E3/polyUb reveals mechanisms of K48-linked Ub chain extension

Mark A Nakasone, Karolina A Majorek, Mads Gabrielsen, Gary J Sibbet, Brian O. Smith, Danny T. Huang (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)
57 Downloads (Pure)

Abstract

Ubiquitin (Ub) chain types govern distinct biological processes. K48-linked polyUb chains target substrates for proteasomal degradation, but the mechanism of Ub chain synthesis remains elusive due to the transient nature of Ub handover. Here, we present the structure of a chemically trapped complex of the E2 UBE2K covalently linked to donor Ub and acceptor K48-linked di-Ub, primed for K48-linked Ub chain synthesis by a RING E3. The structure reveals the basis for acceptor Ub recognition by UBE2K active site residues and the C-terminal Ub-associated (UBA) domain, to impart K48-linked Ub specificity and catalysis. Furthermore, the structure unveils multiple Ub-binding surfaces on the UBA domain that allow distinct binding modes for K48- and K63-linked Ub chains. This multivalent Ub-binding feature serves to recruit UBE2K to ubiquitinated substrates to overcome weak acceptor Ub affinity and thereby promote chain elongation. These findings elucidate the mechanism of processive K48-linked polyUb chain formation by UBE2K.

Original languageEnglish
Pages (from-to)422-431
Number of pages10
JournalNature Chemical Biology
Volume18
Issue number4
Early online date13 Jan 2022
DOIs
Publication statusPublished - Apr 2022

Keywords

  • Polyubiquitin/metabolism
  • Protein Binding
  • Protein Domains
  • Ubiquitin/chemistry
  • Ubiquitin-Conjugating Enzymes/metabolism
  • Ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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