Role of the RING-CH domain of viral ligase mK3 in ubiquitination of non-lysine and lysine MHC I residues

Roger A. Herr, Jennifer Harris, Shengyun Fang, Xiaoli Wang, Ted H. Hansen

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


A plethora of ubiquitin ligases determine the intracellular location and fate of numerous proteins in a substrate-specific manner. However, the mechanisms for these functions are incompletely understood. Most ligases have structurally related RING domains that are critical for ligase activity including the recruitment of ubiquitin conjugating enzymes. Here we probe the function of the RING-CH domain of murine γ-herpesvirus-68 ligase mK3 that functions as an immune evasin by targeting major histocompatibility complex (MHC) class I heavy chains for endoplasmic reticulum-associated degradation (ERAD). Interestingly, mK3 mediates ubiquitin conjugation via ester bonds to S or T residues in addition to conventional isopeptide linkages to K residues. To determine the mechanism of non-K ubiquitination of substrates, we introduced into an mK3 background the RING-CH domains of related viral and cellular MARCH (membrane a ssociated RING-CH) ligases. We found that although a conserved W present in all viral RING-CH domains is critical for mK3 function, sequences outside the RING-CH domain determine whether and which non-lysine substrate residues can be ubiquitinated by mK3. Our findings support the model that viral ligases have evolved a highly effective strategy to optimally orient their RING domain with substrate allowing them to ubiquitinate non-K residues.

Original languageEnglish
Pages (from-to)1301-1317
Number of pages17
Issue number9
StatePublished - 2009


  • MHCI
  • Non-lysine
  • Ubiquitination
  • mK3


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