Active, Recombinant Human UBE2K

Background: Human UBE2K comprises an N-terminal UBC fold (Cys92 active site) and a C-terminal UBA domain (aa 163-214). Crystal and cryo-EM data reveal a monomeric enzyme whose UBA clamps incoming ubiquitin to pre-orient Lys48 for attack, explaining the enzyme’s E3-independent chain elongation. UBE2K assembles unanchored or substrate-linked K48 polymers that flag proteins for 26S proteasomal degradation. It partners with RING E3s such as RNF2 and TRAF6, and ubiquitylates huntingtin, linking it to polyglutamine neurotoxicity. The UBA also enables K48/K63-branched chain synthesis on pre-existing K63 substrates, tuning NF-κB and DNA-damage responses.