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Eukaryotic ubiquitin-like proteins (UBLs) have evolved from prokaryotic sulfur-carrier proteins (SCPs). Ubiquitin related modifier 1 (Urm1) shares biochemical and structural features of UBLs and SCPs and is essential for 2-thiolation of cytoplasmic tRNA. This chemical modification of wobble uridine is highly conserved amongst species and is achieved via Urm1 thiocarboxylation by the non-canonical ubiquitin activating 4 enzyme (Uba4), which contains an E1- and a Rhodanese (RHD) domain. While the RHD catalyzes the last step in Urm1-thiocarboxylate formation, the previous steps in Urm1 activation and the interplay between the two domains have remained elusive. To define the underlying mechanism, we established an Urm1 in vitro thiocarboxylation assay, which combined with structure-function and chemical profiling analyses revealed a critical thioester linkage between Urm1 and Uba4 residue Cys225. This linkage is indispensable for the Urm1 intramolecular transfer between the two domains of Uba4 and it is thus, essential for tRNA thiolation in vivo. These findings contribute to a deeper understanding of UBL evolution.

The Uba4 domain interplay is mediated via a thioester that is critical for tRNA thiolation through Urm1 thiocarboxylation