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2 Domains1
* Department of Immunology, Interfacultary Institute for Cell Biology, and
Interfacultary Institute for Biochemistry, Eberhard-Karls-University Tübingen, Tübingen, Germany
Human CMV infection results in MHC class I down-regulation and induction of NKG2D ligand expression favoring NK recognition of infected cells. However, human CMV-encoded UL16 counteracts surface expression of several NKG2D ligands by intracellular retention. Interestingly, UL16 interacts with MICB, but not with the closely related MICA, and with UL16-binding proteins (ULBP) ULBP1 and ULBP2, which are only distantly related to MICB, but not with ULPB3 or ULBP4, although all constitute ligands for NKG2D. Here, we dissected the molecular basis of MICA-MICB discrimination by UL16 to elucidate its puzzling binding behavior. We report that the UL16-MICB interaction is independent of glycosylation and demonstrate that selective MICB recognition by UL16 is governed by helical structures of the MICB 
2 domain. Transplantation of the MICB 2 domain confers UL16 binding capacity to MICA, and thus, diversification of the MICA 2 domain may have been driven by the selective pressure exerted by UL16.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Deutsche Forschungsgemeinschaft (STE 828/2 to A.S. and GK794 to J.S.).
2 Address correspondence and reprint requests to Dr. Alexander Steinle, Interfakultaeres Institut fuer Zellbiologie, Abteilung Immunologie, Auf der Morgenstelle 15, 72076 Tübingen, Germany. E-mail address: alexander.steinle{at}uni-tuebingen.de
3 Abbreviations used in this paper: HCMV, human CMV; MCMV, mouse CMV; NKG2DL, NKG2D ligand; ULBP, UL16-binding protein; ER, endoplasmic reticulum; sMICA, soluble MICA; PNGase F, peptide:N-glycanase F.
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