Differential NKG2D binding to highly related human NKG2D ligands ULBP2 and RAET1G is determined by a single amino acid in the alpha2 domain

Mareike Wittenbrink, Jessica Spreu, Alexander Steinle
European Journal of Immunology 2009, 39 (6): 1642-51
The activating NK cell receptor NKG2D binds to numerous stress-induced cell surface glycoproteins with MHC class I-related ectodomains. In humans, NKG2D ligands (NKG2DL) are members of the MHC-encoded MIC and non-MHC-encoded ULBP families of proteins. The redundancy of NKG2DL raises questions about unique features associated with individual NKG2DL. The ULBP family member RAET1G contains an ectodomain highly related to ULBP2, but is unique by virtue of an extended cytoplasmic domain. Since RAET1G is poorly characterized, we studied expression and functional interactions of RAET1G in comparison to ULBP2. RAET1G transcripts were detected in most human tissues with an overall expression pattern similar to ULBP2. However, although ULBP2 strongly binds both NKG2D and the immunoevasive human cytomegalovirus glycoprotein UL16, RAET1G only weakly interacts with NKG2D and does not bind UL16. Differential binding capacities of the two highly related ectodomains are mainly due to a substitution of a conserved amino acid in the alpha2 domain of RAET1G. In functional terms, the reduced apparent avidity of RAET1G for NKG2D results in a less-efficient NKG2D down-regulation and NK degranulation. Altogether, RAET1G, like ULBP2, appears broadly expressed, but exhibits a lower apparent avidity for NKG2D due to a mutation in the center of the MHC-like fold.

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