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Role of the RING‐CH Domain of Viral Ligase mK3 in Ubiquitination of Non‐Lysine and Lysine MHC I Residues
Author(s) -
Herr Roger A.,
Harris Jennifer,
Fang Shengyun,
Wang Xiaoli,
Hansen Ted H.
Publication year - 2009
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2009.00946.x
Subject(s) - ubiquitin ligase , ubiquitin , biology , ubiquitin protein ligases , dna ligase , microbiology and biotechnology , ring finger , lysine , nedd4 , function (biology) , biochemistry , ring finger domain , endoplasmic reticulum associated protein degradation , zinc finger , enzyme , amino acid , gene , transcription factor
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 ( m embrane a ssociated R ING‐ 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.