Ubiquitination of substrates by esterification

Abstract

Post-translational modification by ubiquitination determines intracellular location and fate of numerous proteins, thus impacting a diverse array of physiologic functions. Past dogma has been that ubiquitin was only coupled to substrates by isopeptide bonds to internal lysine residues or less frequently peptide bonds to the N-terminus. Enigmatically, however, several proteins lacking lysines had been reported to retain ubiquitin-dependent fates. Resolution of this paradox was afforded by recent observations that ubiquitination of substrates can also occur on cysteine or serine and threonine residues by thio- or oxy-ester bond formation, respectively (collectively called esterification). Although chemically possible, these bonds were considered too labile to be of physiological relevance. In this review we discuss recent evidence for the ubiquitination of protein substrates by esterification and speculate on its mechanism and its physiological importance.

Figure 1

A. Schema c showing different chemical bonds between Ub and substrates. The upper panel shows pep de and isopep de linkages between Ub (Pink balls) and protein substrates (Gray ovals). Ub coupling on the N-terminus is shown on the le# and Ub coupling to an internal K residue is shown on the right. The lower panel of A shows thio- and oxy-ester linkages of Ub to C or S/T residues of substrates, respec vely. B. Schema c model showing how viral ligase mK3 (blue) interacts with Ube2j2 (green) to ubiqui nate S residues on the cytosolic tail of MHCI heavy chain (HC) (gray), then build a Lys48 (K48) linked chain. The adaptor proteins TAP/tapasin that confer substrate specificity by orien ng mK3/Ube2j2 with the HC tail are shown in yellow/tan.