A C-terminal glutamine recognition mechanism revealed by E3 ligase TRIM7 structures

The E3 ligase TRIM7 has emerged as a critical player in viral infection and pathogenesis. However, the mechanism governing the TRIM7-substrate association remains to be defined. Here we report the crystal structures of TRIM7 in complex with 2C peptides of human enterovirus. Structure-guided studies reveal the C-terminal glutamine residue of 2C as the primary determinant for TRIM7 binding. Leveraged by this finding, we identify norovirus and SARS-CoV-2 proteins, and physiological proteins, as new TRIM7 substrates. Crystal structures of TRIM7 in complex with multiple peptides derived from SARS-CoV-2 proteins display the same glutamine-end recognition mode. Furthermore, TRIM7 could trigger the ubiquitination and degradation of these substrates, possibly representing a new Gln/C-degron pathway. Together, these findings unveil a common recognition mode by TRIM7, providing the foundation for further mechanistic characterization of antiviral and cellular functions of TRIM7.

Automated summary

The E3 ligase TRIM7 plays a critical role in viral infection and pathogenesis. The association between TRIM7 and its substrates is determined by the C-terminal glutamine residue of 2C peptides. New substrates of TRIM7, including norovirus and SARS-CoV-2 proteins, have been identified. Crystal structures of TRIM7 in complex with peptides from SARS-CoV-2 proteins reveal a common recognition mode.