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. 2012 Nov;19(11):1176-81.
doi: 10.1038/nsmb.2396. Epub 2012 Oct 7.

Crystal structure of adenovirus E3-19K bound to HLA-A2 reveals mechanism for immunomodulation

Lenong Li  1 , Yasameen Muzahim, Marlene Bouvier
Affiliations

Crystal structure of adenovirus E3-19K bound to HLA-A2 reveals mechanism for immunomodulation

Lenong Li et al. Nat Struct Mol Biol. 2012 Nov.

Abstract

E3-19K binds to and retains MHC class I molecules in the endoplasmic reticulum, suppressing anti-adenovirus activities of T cells. We determined the structure of the adenovirus serotype 2 (Ad2, species C) E3-19K-HLA-A2 complex to 1.95-Å resolution. Ad2 E3-19K binds to the N terminus of the HLA-A2 groove, contacting the α1, α2 and α3 domains and β(2)m. Ad2 E3-19K has a unique structure comprising a large N-terminal domain, formed by two partially overlapping β-sheets arranged in a V shape, and a C-terminal α-helix and tail. The structure reveals determinants in E3-19K and HLA-A2 that are important for complex formation; conservation of some of these determinants in E3-19K proteins of different species and MHC I molecules of different loci suggests a universal binding mode for all E3-19K proteins. Our structure is important for understanding the immunomodulatory function of E3-19K.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
The structure of Ad2 E3-19K–HLA-A2. (a) Ribbon representation of the structure of Ad2 E3-19K–HLA-A2: E3-19K, cyan; heavy chain (α1-, α2-, and α3-domains), yellow; β2m, green; HIV-1 Tax (LLFGYPVYV) peptide, orange; and disulfide bond, magenta. The N- and C-termini of Ad2 E3-19K are labeled. (b) Ribbon representation of the structure of liganded Ad2 E3-19K (top) and its topology diagram (below). The N-terminal domain (residues 1–78), α-helix (residues 79–93), and tail (residue 94–100) are indicated. The disulfide bonds are shown in magenta. The β strands A, B, C, C′, E, F, and G, and N1- and C100-termini are labeled. The β strands are represented by arrows and the α-helix is shown as a cylinder. The two disulfide bonds are indicated by dashed lines.
Figure 1
Figure 1
The structure of Ad2 E3-19K–HLA-A2. (a) Ribbon representation of the structure of Ad2 E3-19K–HLA-A2: E3-19K, cyan; heavy chain (α1-, α2-, and α3-domains), yellow; β2m, green; HIV-1 Tax (LLFGYPVYV) peptide, orange; and disulfide bond, magenta. The N- and C-termini of Ad2 E3-19K are labeled. (b) Ribbon representation of the structure of liganded Ad2 E3-19K (top) and its topology diagram (below). The N-terminal domain (residues 1–78), α-helix (residues 79–93), and tail (residue 94–100) are indicated. The disulfide bonds are shown in magenta. The β strands A, B, C, C′, E, F, and G, and N1- and C100-termini are labeled. The β strands are represented by arrows and the α-helix is shown as a cylinder. The two disulfide bonds are indicated by dashed lines.
Figure 2
Figure 2
Hydrophobic core of Ad2 E3-19K. Ribbon representation of the structure of liganded Ad2 E3-19K showing the side chain of the core-forming residues (magenta) (some side chains are labeled for clarity). Core-forming residues (>90% buried) were determined by using SPDBV. The β strands A, B, C, C′, E, F, and G, and N- and C-termini are labeled.
Figure 3
Figure 3
Interaction surface between Ad2 E3-19K and HLA-A2. Interaction sites 1, 2, 3 and 4 of Ad2 E3-19K–HLA-A2 are shown in separate panels using the same color code as in Figure 1(a). Nitrogen, oxygen and sulfur atoms are colored blue, red, and light orange, respectively. Hydrogen bonds (distance ≤ 3.5 Å) and salt bridges are indicated by dashed green lines, hydrophobic contacts (distance < 4.0 Å) are represented by dashed magenta lines. Water molecules are shown as red spheres. The β strands of Ad2 E3-19K and α1-, α2-, α3-domains of the heavy chain are labeled.
Figure 4
Figure 4
Electrostatic properties of interacting surfaces in Ad2 E3-19K and HLA-A2. Electrostatic surfaces of Ad2 E3-19K and HLA-A2 at interaction sites 1, 2, 3, and 4 (marked by dashed lines): electronegative (red, −1.000 kTe−1), electropositive (blue, +1.000 kTe−1), and apolar (white). Conserved contact residues in Ad2 E3-19K and HLA-A2 at site 1 (Lys27 and Glu53, respectively) and site 2 (Lys42 and Glu177, respectively) that form salt bridges are labeled. The α1-, α2-, and α3-domains of the heavy chain and β2m are labeled.
Figure 5
Figure 5
Conserved residues in Ad2 E3-19K. Strictly (blue) and highly (cyan) conserved residues are mapped in the structure of Ad2 E3-19K. The side chains of strictly and highly conserved residues at sites 1 (Glu18, Leu25, Lys27), 2 (Glu18, Lys42), 3 (Leu95), and 4 (Met89, Gln92, Tyr93) are indicated; nitrogen, oxygen and sulfur atoms are colored blue, red, and light orange, respectively. The positions of Thr14 and Met82 side chains, which are important for MICA and MICB interaction, are indicated by dashed arrows. The β strands A, B, C, C′, E, F, and G, and N- and C-termini are labeled.
Figure 6
Figure 6
Amino acid sequence alignment at the four interaction sites. Alignment of HLA-A2 and consensus HLA-A, -B, and -C heavy chain sequences at sites 1, 2, and 3. Interaction site 4 on β2m is also indicated. Capital letters designate contact residues at each of the four sites (see legend of Figure 3). Consensus sequences were obtained from the IMGT-HLA Sequence Database (www.ebi.ac.uk/imgt/hla/align.html).
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