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Q: Ubiquitin (UB) is a protein modifier that regulates many essential cellular processes. To initiate protein modification by UB, the E1 enzyme activates the C-terminal carboxylate of UB to launch its transfer through the E1-E2-E3 cascade onto target proteins. In this study, we used phage display to profile the specificity of the two human E1 enzymes, Ube1 and Uba6, towards the Cterminal sequence of UB ending with 71 LRLRGG 76 . Phage selection revealed that while Arg72 of UB is absolutely required for E1 recognition, UB residues at positions 71, 73 and 74 can be replaced with bulky aromatic side chains, and Gly75 of UB can be changed to Ser, Asp and Asn for efficient E1 activation. We have thus found that the E1 enzymes have substantial promiscuity regarding the UB C-terminal sequence. The UB variants from phage selection can also be transferred from E1 to E2 enzymes, however, they are blocked from further transfer to the E3 enzymes. This suggests that the C-terminal sequence of UB is important for its discharge from E2 and subsequent transfer to E3. In addition, we observed that the Leu73Phe and Leu73Tyr single mutants of UB are resistant to cleavage by deubiquitinating enzymes (DUBs), although they can be assembled by the E1-E2-E3 cascade into poly-UB chains, thus indicating differences in UB Cterminal specificities between the E1 and DUBs. Consequently these UB mutants may provide stability to UB polymers attached to cellular proteins and facilitate the elucidation of the biological signals encoded in the UB chains. Ubiquitin (UB) is a 76-residue protein that is attached to cellular proteins through an isopeptide bond between the C-terminal carboxylate of UB and the -amino group of a Lys residue on the modified protein. 1 Protein modifications by UB are associated with a myriad of cellular functions, including regulation of protein degradation, designation of protein
A:
Specificity of the E1-E2-E3 Enzymatic Cascade for Ubiquitin C- terminal Sequences Identified by Phage Display HHS Public Access Author manuscript Supplementary Material Refer to Web version on PubMed Central for supplementary material