Abstract
FAT10 conjugation, a post-translational modification analogous to ubiquitination, specifically requires UBA6 and UBE2Z as its activating (E1) and conjugating (E2) enzymes. Interestingly, these enzymes can also function in ubiquitination. We have determined the crystal structure of UBE2Z and report how the different domains of this E2 enzyme are organized. We further combine our structural data with mutational analyses to understand how specificity is achieved in the FAT10 conjugation pathway. We show that specificity toward UBA6 and UBE2Z lies within the C-terminal CYCI tetrapeptide in FAT10. We also demonstrate that this motif slows down transfer rates for FAT10 from UBA6 onto UBE2Z.
Highlights
FAT10 conjugation, a post-translational modification analogous to ubiquitination, requires UBA6 and UBE2Z as its activating (E1) and conjugating (E2) enzymes
Whereas FAT10 has been described to function only with UBA6 as its sole activating enzyme [14] and with UBE2Z as its conjugating enzyme [16], these E1 and E2 enzymes are involved in ubiquitination reactions [14, 15]
UBE2Z has been shown to function with UBA6 but not with UBA1 [15]
Summary
FAT10 conjugation, a post-translational modification analogous to ubiquitination, requires UBA6 and UBE2Z as its activating (E1) and conjugating (E2) enzymes. We show in biochemical assays that a specific LB loop region and the N-terminal extension in UBE2Z are essential for selectivity toward UBA6 and demonstrate that the FAT10 C-terminal tail CYCI motif hinders both FAT10 activation and transfer to the E2 enzyme.
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