Structure of the Adenovirus Type 4 (Species E) E3-19K/HLA-A2 Complex Reveals Species-Specific Features in MHC Class I Recognition

Abstract

Adenoviruses (Ads) subvert MHC class I antigen presentation and impair host anti-Ad cellular activities. Specifically, the Ad-encoded E3-19K immunomodulatory protein targets MHC class I molecules for retention within the endoplasmic reticulum (ER) of infected cells. Here, we report the x-ray crystal structure of the Ad type 4 (Ad4) E3-19K of species E bound to HLA-A2 at 2.64 Å resolution. Structural analysis shows that Ad4 E3-19K adopts a tertiary fold that is shared only with Ad2 E3-19K of species C. A comparative analysis of the Ad4 E3-19K/HLA-A2 structure with our x-ray structure of Ad2 E3-19K/HLA-A2 identifies species-specific features in HLA-A2 recognition. Our analysis also reveals common binding characteristics that explain the promiscuous, and yet high-affinity, association of E3-19K proteins with HLA-A and -B molecules. We also provide structural insights into why E3-19K proteins do not associate with HLA-C molecules. Overall, our study provides new information into how E3-19K proteins selectively engage with MHC I to abrogate antigen presentation and counteract activation of CD8+ T-cells. The significance of MHC I antigen presentation for controlling viral infections, and the threats of viral infections in immunocompromised patients, underline our efforts to characterize viral immunoevasins such as E3-19K.

Immune evasion by adenoviruses: a window into host–virus adaptation

“…). This binding mode was also seen in the X‐ray structure of the HAdV‐E4 E3‐19K/HLA‐A2 complex . These structures provided critical information to understand that the conserved residues form a tightly packed hydrophobic core essential to maintain the unique tertiary fold of E3‐19K (Fig.…”

Deep analysis of Loop L1 HVRs1-4 region of the hexon gene of adenovirus field strains isolated in Poland

“…In Loop L3 there are no such determinants [ 3 ]. Lenong, 2016 [ 4 ] indicated that three structure of Ad type2 (Ad2) of species CE3-19K/HLA-A2 complex showed the adaptation of a novel tertiary fold, and uses a new binding surface on HLA-A2. The adenoviruses encoded E3-19K immunomodulatory protein targets MHC class I molecules for retention within the endoplasmic reticulum (ER).…”

Homology-based loop modeling yields more complete crystallographic protein structures

“…As shown in Fig. 7(b), a strand is missing from the -sheet of the 3 subunit of HLA in PDB entry 5iro (Li et al, 2016), a protein complex of Adenovirus type 4 E3-19K with HLA class I histocompatibility antigen. By optimization of the structure model by PDB-REDO including loop building, the R/R free drops from 0.220/0.236 to 0.182/ 0.190.…”