Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2

Many persistent viruses have evolved the ability to subvert MHC class I ant igen presentation. Indeed, human cytomegalovirus (HCMV) encodes at least fo ur proteins that down-regulate cell-surface expression of class I. The HCMV unique short (US)2 glycoprotein binds newly synthesized class I molecules within the endoplasmic reticulum (ER) and subsequently targets them for pro teasomal degradation. We report the crystal structure of US2 bound to the H LA-A2/Tax peptide complex. US2 associates with HLA-AZ at the junction of th e peptide-binding region and the (alpha3 domain, a novel binding surface on class I that allows US2 to bind independently of peptide sequence. Mutatio n of class I heavy chains confirms the importance of this binding site in v ivo. Available data on class I-ER chaperone interactions indicate that chap erones would not impede US2 binding. Unexpectedly. the US2 ER-luminal domai n forms an Ig-like fold. A US2 structure-based sequence alignment reveals t hat seven HCMV proteins, at least three of which function in immune evasion , share the same fold as US2. The structure allows design of further experi ments to determine how US2 targets class I molecules for degradation.