The structure of cytomegalovirus immune modulator UL141 highlights structural Ig-fold versatility for receptor binding.

摘要: Natural killer (NK) cells are critical components of the innate immune system as they rapidly detect and destroy infected cells. To avoid recognition to allow long-term persistence in host, Human cytomegalovirus (HCMV) has evolved a number genes evade or inhibit effector pathways. In particular, UL141 can cell-surface expression both NK cell-activating ligand CD155 well TRAIL death receptors (TRAIL-R1 TRAIL-R2). The crystal structure unliganded HCMV refined 3.25 A resolution allowed analysis its head-to-tail dimerization interface. A ‘dimerization-deficient’ mutant (ddUL141) was further designed, which retained ability bind TRAIL-R2 while losing cross-­link two receptor monomers. Structural comparison with bound identified mobile loop that makes intimate contacts upon engagement. Superposition Ig-like domain on T-cell immunoreceptor Ig ITIM domains (TIGIT) revealed potentially engage similar TIGIT by using C′C′′ GF loops. Further mutations binding site (Q63R F128R) abrogated binding, suggesting is viral mimic TIGIT, it targets same ‘lock-and-key’ interactions. Sequence alignment gene orthologues also showed conservation this highly hydrophobic (L/A)X 6G ‘lock’ motif for patches, these host–receptor interactions evolutionary conserved.