8st7
Structure of E3 ligase VsHECT bound to ubiquitin
Structural highlights
FunctionUBC_HUMAN Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[1] [2] Publication Abstract from PubMedHECT E3 ubiquitin (Ub) ligases direct their modified substrates toward a range of cellular fates dictated by the specific form of monomeric or polymeric Ub (polyUb) signal that is attached. How polyUb specificity is achieved has been a longstanding mystery, despite extensive study ranging from yeast to human. Two outlying examples of bacterial "HECT-like" (bHECT) E3 ligases have been reported in the human pathogens Enterohemorrhagic Escherichia coli and Salmonella Typhimurium, but what parallels can be drawn to eukaryotic HECT (eHECT) mechanism and specificity had not been explored. Here, we expanded the bHECT family and identified catalytically active, bona fide examples in both human and plant pathogens. By determining structures for three bHECT complexes in their primed, Ub-loaded states, we resolved key details of the full bHECT Ub ligation mechanism. One structure provided the first glimpse of a HECT E3 ligase in the act of ligating polyUb, yielding a means to rewire the polyUb specificity of both bHECT and eHECT ligases. Through studying this evolutionarily distinct bHECT family, we have not only gained insight into the function of key bacterial virulence factors but also revealed fundamental principles underlying HECT-type Ub ligation. Bacterial mimicry of eukaryotic HECT ubiquitin ligation.,Franklin TG, Brzovic PS, Pruneda JN bioRxiv. 2023 Jun 5:2023.06.05.543783. doi: 10.1101/2023.06.05.543783. Preprint. PMID:37333152[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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