Research Article

Structure of the herpes simplex virus 1 capsid with associated tegument protein complexes

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Science  06 Apr 2018:
Vol. 360, Issue 6384, eaao7298
DOI: 10.1126/science.aao7298
  • Structure of the HSV-1 capsid with capsid-associated tegument proteins.

    Surface view of a 4.2-Å resolution map of the icosahedral capsid, with a single facet shown in color. The structure of the vertex region (magnified view) was improved to 3.5-Å resolution by subparticle refinement. P, peripentonal; C, center; E, edge; Ta to Te, heterotrimeric triplexes composed of Tri1, Tri2A, and Tri2B.

  • Fig. 1 Cryo-EM reconstruction and atomic modeling of the HSV-1 capsid.

    (A) Radially colored cryo-EM density map of the HSV-1 capsid viewed along a threefold axis. Fivefold, threefold, and twofold axes are denoted by a pentagon, triangle, and oval, respectively. (B) Magnified view of one facet of the icosahedral capsid with structural components differentially colored. The density of triplex Tf at the center is not shown. (C) A schematic representation of one asymmetric unit (shaded) of the capsid. An extra copy of triplex Te (unshaded) from an adjacent asymmetric unit is shown to depict that triplex pair Tb-Te has a similar configuration as Ta-Tc, thus providing a second potential binding site for the CATC (11, 17). The enlarged red and blue triangle shows the heterotrimeric nature of a triplex. a.a., amino acid. (D) Atomic models of individual capsid or tegument proteins in rainbow-colored ribbon (from blue at the N terminus to red at the C terminus). Numbers denote chain termini or flexible segments that are not modeled. a.a., amino acid.

  • Fig. 2 Structure of the CATC.

    (A) Cryo-EM densities of the CATC surrounding a penton vertex. The density map was low-pass filtered to 6-Å resolution to show the flexible pUL25 head region. (B) Magnified view of a segmented-out CATC unit from the dashed square in (A), showing its composition. (C) Fitting of two copies of pUL25 C-terminal region crystal structure (PDB 2F5U) (22) into the bi-lobed head region of CATC. The contour level for the pUL25 head region in (A) to (C) was 1.5δ (where δ is the standard deviation) and that of the rest was 3δ. (D and E) Top view (D) and side view (E) of CATC interacting with underlying capsid components, shown with atomic models. On the left in (E) is a magnified view of the interface between the CATC and triplex Tc. Hydrophobic side chains of the pUL25 dimer, Tri1, and Tri2B involved in the interactions are highlighted. (F and G) Domain organization of pUL17 (F) and pUL25 (G). (H and I) The five-helix bundle viewed from the top of the capsid (H) or along the center of the coiled coil (I). In (H), side chains are shown for hydrophobic residues in the center of the helix bundle (top), with their identities marked (grayed) in the sequence (bottom). The arrowhead in (H) points to the position in the pUL25 sequence where the hydrophobic residue distribution pattern breaks. Nʹ, N terminus; Cʹ, C terminus.

  • Fig. 3 Structure of the triplex.

    (A) Distribution of triplexes in the MCP network. (B) Magnified view of a triplex Tb as viewed from the outside of the capsid. (C to F) Detailed structures of triplex Tb (C) and its components Tri1 (D), Tri2A (E), and Tri2B (F). Dotted curves in (C) and (D) denote the N-terminal region of Tri1 that was not modeled because of its flexibility. (G) Superposition of Tri2A and Tri2B showing constant trunk domains and conformational differences in their embracing-arm domains. (H) Tri2A and Tri2B embrace each other with their embracing-arm domains to form a dimer. (I) The Tri1 insertional arm binding on top of the Tri2 dimer and the Tri1-Tri2B intermolecular disulfide bond (shown in magnified view) stabilize the triplex structure. (J) Architectural similarities between HSV-1 triplex (top) and the gpD trimer of phage λ (bottom, PDB 1C5E) (26). Both are viewed from the inside of the capsid. (K) Same topology of β strands among gpD, Tri1, and Tri2. Corresponding β strands are colored in the same way and numbered one to eight, from Nʹ to Cʹ. (L) Cryo-EM density of triplex Tb in the same orientation as (J), showing the tri-lobed density of the flexible Tri1 N anchor (gray), which penetrates through the capsid floor and anchors the entire triplex to the capsid shell, as depicted in (C).

  • Fig. 4 SCP and MCP network interactions.

    (A) Domain organization in a hexon MCP. (B and C) SCP binds the upper domain of hexon MCP (B), and six copies of SCP form a gear-shaped ring crowning and stabilizing the hexon (C). (D and E) Part of the MCP network viewed from the outside (D) or the inside (E) of the capsid. Pen, penton. (F to I) Three types of network interactions among hexon MCPs. (H) and (I) show the individual structures that make up (G). The type I interaction is an intracapsomeric augmentation of β strands from adjacent MCPs [P2 and P3 in (F)] in the same capsomer. Type II and type III are intercapsomeric interactions among two pairs of MCPs [P2-P3 and C5-C6 in (G)] diagonally across the local twofold axis [ovals in (G) to (I)]. The type III interaction builds on and fortifies the type I interaction [see C5 N lasso in (F)]. The two dimerization domains joined by a type II interaction (I) also sit atop a pair of type III interactions, when looking from the inside of the capsid (G), and prevent the two N lassos [C5 and P2 N lassos in (G) and (H)] from unwinding. (J and K) Interactions between penton MCPs and the P1 and P6 hexon MCPs are different from the canonical hexon MCP network interactions [compare (J) and (G), (K) and (H)]. (L) Cryo-EM density at the penton area viewed from the inside of the capsid. The five copies of penton MCP are differently colored, whereas all P1 MCPs are colored in gold.

  • Movie 1 Overall structure and high-resolution features of the HSV-1 capsid icosahedral reconstruction.
  • Movie 2 High-resolution features in the 3.5-Å resolution subparticle reconstruction of the HSV-1 capsid vertex region.
  • Movie 3 Fitting of two copies of the pUL25 C-terminal region crystal structure into the bi-lobed head region of CATC.
  • Movie 4 Structure of the CATC and its interactions with the underlying capsid components.
  • Movie 5 MCP network interactions in the capsid floor.

Supplementary Materials

  • Structure of the herpes simplex virus 1 capsid with associated tegument protein complexes

    Xinghong Dai and Z. Hong Zhou

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Figs. S1 to S9 
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