Cytomegalovirus gpUL141 exhibits unique receptor-binding domain to inhibit cell surface expression of CD155 and TRAIL death receptors

I. Nemčovičová¹ and D. M. Zajonc²

¹Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Dúbravská cesta 9, SK 84505, Bratislava, Slovakia

²Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, CA 92037, La Jolla, USA

E-mail: viruivka@savba.sk

To avoid immune recognition and to allow for longtime persistence in the host, human cytomegalovirus (HCMV) evolved a number of genes to evade or inhibit immune effector pathways. Especially glycoprotein (gp)UL141 can inhibit cell surface expression of both the natural killer (NK) cell activating ligand CD155 as well as TRAIL death receptors (TRAIL-R1 and -R2). The crystal structure of unliganded HCMV UL141 refined to 3.25 Å resolution allowed us to analyze its head-to-tail dimerization interface. We further designed a 'dimerization deficient' mutant of UL141 (ddUL141), which retained the ability to bind to TRAIL-R2 or CD155, while having lost the ability to cross-link two receptor monomers. Structural comparison of unliganded UL141 with UL141 that is bound to TRAIL-R2 further identified a mobile loop that makes intimate contacts with TRAIL-R2 upon receptor engagement. Superposition of the Ig-domain of UL141 on the CD155 ligand T-cell-Ig-and-ITIM-domain (TIGIT) revealed that UL141 can potentially engage CD155 similar to TIGIT by using the C’C” and GF loop. Further mutations in the TIGIT binding site of CD155 (Q63R and F128R) abrogated UL141 binding suggesting that the Ig domain of UL141 is a viral mimic of TIGIT, as it targets the same binding site on CD155 using similar 'lock-and-key' interactions. Sequence alignment of UL141 gene and its orthologs also showed conservation in this highly hydrophobic (L/A)X₆G 'lock' motif for CD155 binding as well as conservation along TRAIL-R2 binding patches, suggesting these host receptor interactions are evolutionary conserved.