Crystal structures of two bacterial HECT-like E3 ligases in complex with a human E2 reveal atomic details of pathogen-host interactions.
In eukaryotes, ubiquitination is an important posttranslational process achieved through a cascade of ubiquitin-activating (E1), conjugating (E2), and ligase (E3) enzymes. Many pathogenic bacteria deliver virulence factors into the host cell that function as E3 ligases. How these bacterial "Trojan horses" integrate into the eukaryotic ubiquitin system has remained a mystery. Here we report crystal structures of two bacterial E3s, Salmonella SopA and Escherichia coli NleL, both in complex with human E2 UbcH7. These structures represent two distinct conformational states of the bacterial E3s, supporting the necessary structural rearrangements associated with ubiquitin transfer. The E2-interacting surface of SopA and NleL has little similarity to those of eukaryotic E3s. However, both bacterial E3s bind to the canonical surface of E2 that normally interacts with eukaryotic E3s. Furthermore, we show that a glutamate residue on E3 is involved in catalyzing ubiquitin transfer from E3 to the substrate, but not from E2 to E3. Together, these results provide mechanistic insights into the ubiquitin pathway and a framework for understanding molecular mimicry in bacterial pathogenesis.
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
David Yin-wei
DY
Lin
Jianbo
J
Diao
Jue
J
Chen
D000596:Amino Acids / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry*; D055162:Biocatalysis; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000737:chemistry*; D054884:Host-Pathogen Interactions; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation; D012475:Salmonella / Q000201:enzymology*; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry*
D000596:Amino Acids; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; C079437:UBE2L3 protein, human; D044763:Ubiquitin-Conjugating Enzymes; C555414:NleL protein, E coli; D044767:Ubiquitin-Protein Ligases; C060971:SopA protein, Bacteria