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Extensive subunit contacts underpin herpesvirus capsid stability and interior-to-exterior allostery

Nature Structural & Molecular Biology volume 23, pages 531–539 (2016)Cite this article

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Abstract

The herpesvirus capsid is a complex protein assembly that includes hundreds of copies of four major subunits and lesser numbers of several minor proteins, all of which are essential for infectivity. Cryo-electron microscopy is uniquely suited for studying interactions that govern the assembly and function of such large functional complexes. Here we report two high-quality capsid structures, from human herpes simplex virus type 1 (HSV-1) and the animal pseudorabies virus (PRV), imaged inside intact virions at ~7-Å resolution. From these, we developed a complete model of subunit and domain organization and identified extensive networks of subunit contacts that underpin capsid stability and form a pathway that may signal the completion of DNA packaging from the capsid interior to outer surface, thereby initiating nuclear egress. Differences in the folding and orientation of subunit domains between herpesvirus capsids suggest that common elements have been modified for specific functions.

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Figure 1: Architecture of the HSV-1 capsid.
Figure 2: HSV-1 and PRV density maps.
Figure 3: Organization of the major capsid protein VP5.
Figure 4: Interior capsid density.
Figure 5: Triplex organization.
Figure 6: The CVSC subunit pUL25 depends on pUL17 to bind capsids.
Figure 7: pUL25 localization and contacts.
Figure 8: Organization of the CVSC molecule.
Figure 9: CVSC location is limited by triplex orientation and hexon crowding.

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Acknowledgements

The authors thank K. Sader (FEI) for expert technical assistance with collecting the PRV data set, and H. Lopez, T. Neef, and J. Yoder for technical assistance in the early stages of image analysis. We gratefully acknowledge W. Busing and J. Balkovec of FEI for assisting with access to a Krios microscope for data collection, and R. Duda for his comments on the manuscript. J. Brown (University of Virginia) kindly provided an anti-pUL25 mouse monoclonal antibody, and J. Baines (Cornell University) provided an anti-pUL17 chicken polyclonal antibody. This work was supported by NIH grants R01AI089803 (J.F.C. and F.L.H.) and R56AI060836 (F.L.H.).

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Authors and Affiliations

  1. Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Alexis Huet, Alexander M Makhov & James F Conway

  2. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Jamie B Huffman & Fred L Homa

  3. Apps Lab, FEI Europe, Eindhoven, the Netherlands

    Matthijn Vos

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  1. Alexis Huet
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  2. Alexander M Makhov
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Contributions

J.F.C. and F.L.H. developed the concepts and experiments; J.B.H. and F.L.H. prepared samples and performed biochemistry; A.M.M. prepared grids; M.V. and J.F.C. developed microscopy procedures and collected data; A.H. and J.F.C. performed data analyses and interpretation; J.F.C., F.L.H. and A.H. prepared the manuscript, which was edited by A.M.M. and M.V.

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Correspondence to James F Conway.

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Integrated supplementary information

Supplementary Figure 1 Location of the mAb 6F10 epitope in capsids.

The epitope of monoclonal antibody, mAb 6F10, was mapped to residues A862–H880 of the HSV-1 major capsid protein VP5 by immunoblotting experiments, and the capsid-antibody complex visualized by cryoEM of 2M GuHCl-treated B-capsids, called “G-capsids” (Newcomb, W.W. & Brown, J.C., J Virol. 65, 613-20, 1991), that had been incubated with antibody (Spencer, J.V. et al., Virology 228, 229-35, 1997). G-capsids have lost pentons and the hexon-capping VP26 molecules as well as peripentonal triplexes and internal scaffolding domains (Booy, F.P. et al., Proc Natl Acad Sci U S A., 91, 5652-6, 1994). Consequently the VP5 epitope is present only in the uncapped hexons, and mAb density was observed near the tips of these hexons, just inside the openings of the trans-capsomeric channels (Spencer, J.V. et al., Virology 228, 229-35, 1997). The fit of the VP5 upper domain fragment (yellow ribbons structure) is shown for (a) the penton, and (b) a hexon of the HSV-1 capsid map, with the mAb 6F10 epitope colored in red. The position of the epitope in our fit, on the exterior rim of the trans-axial capsomer channel that runs through to the interior of the capsid, is consistent with the localization by antibody, providing conclusive validation of our cryoEM density maps. We also predict that pentons with epitopes exposed may bind mAb 6F10 more avidly than hexons where access to the epitope is partially blocked by the VP26 molecule (colored green).

Supplementary Figure 2 Estimating resolution of cryo-EM density maps.

(a) Fourier Shell Correlation (van Heel, M., Ultramicroscopy 48, 95-100, 1987) plots drop below 0.3 at 6.8 Å resolution for the HSV-1 map, and 7.1 Å for the PRV map – we use this level as a compromise between the overly-conservative 0.5, and the “gold-standard” value of 0.143 (Scheres, S.H. & Chen, S., Nat Methods 9, 853-4, 2012; Henderson, R. et al., Structure 20, 205-14, 2012). (b) The VP5 upper domain crystal structure (PDB 1NO7 – Bowman, B.R., et al, EMBO J. 22, 757-65, 2003) in ribbons form colored as a rainbow from E484 (blue) to T1054 (red), and in yellow as fit into the HSV-1 cryoEM density (blue translucent surface). (c) Surface renditions of the atomic model (PDB 1NO7) with different resolution limits applied, as indicated, using the “molmap” function of UCSF Chimera (Pettersen, E.F. et al., J Comput Chem. 25, 1605-12, 2004) based on the “pdb2mrc” program in the EMAN package (Tang, G. et al., J Struct Biol. 157, 38-46, 2007). Comparison of various features with the cryoEM surface in (b) supports the resolution estimated in (a).

Supplementary Figure 3 Organization of the major capsid protein VP5.

(a) Secondary structure prediction with PSIPRED (Jones, D.T, J Mol Biol. 292, 195-202, 1999) together with the constraint of the upper domain crystal fragment location suggests an organization of the VP5 protein as depicted, with the lower and middle domains at either end, bracketing the upper domain. Elements of the HK97-like fold that are consistent with the lower domain correspond well with the secondary structure predicted for the VP5 N-terminal, excepting an insertion (extra density 1: ~200–280) and the transition through the middle domain (~441–483) to the onset of the upper domain fragment. (b) The N-terminal-most 50 amino acids are proposed to form the sub-penton tubes visualized in the HSV density map (red) and the curved tubes beneath hexons (see Fig. 4 in the main text). The PSIPRED prediction for this region includes a 20-residue helix. (c) Several of the density elements are superimposed on our VP5 lower domain model (see Fig. 3b in the main text) including regions corresponding to the phage HK97 capsid protein model. (d) The C-terminus of the upper domain fragment (PDB 1NO7 – Bowman, B.R., et al, EMBO J. 22, 757-65, 2003) leads into a region predicted to be β-rich, corresponding with a feature of the HSV-1 density map as indicated. The remaining middle domain density is difficult to interpret in terms of connectivity and secondary structure elements, consistent with the paucity of helix predicted for the remainder of VP5 until the C-terminal-most ~50 residues.

Supplementary Figure 4 Secondary-structure prediction for pUL25, pUL17, and pUL36 sequences from HSV-1.

Amino acid sequences were analyzed by PSIPRED (Jones, D.T, J Mol Biol. 292, 195-202, 1999) using the server at the UCL Department of Computer Science (Buchan, D.W., et al, Nucleic Acids Res. 41, W349-57, 2013). Purple shading indicates prediction for α-helix, while yellow is for β-strands. (a) pUL25, where the N-terminal 133 residues not included in the crystal structure (Bowman, B.R. et al., J Virol. 80, 2309-17, 2006) reveal the likelihood of adopting a 60-residue helix (H1), consistent with the length of the CVSC helical bundle. (b) pUL17 includes several regions likely to be helical and possibly contributing two parts to the CVSC bundle domain. Since the motif is likely to be a helix-turn-helix, with no significant domain at the turn, we favor the helices indicated (H2 and H3). (c) pUL36 C-terminal region has one candidate (H4) for interacting with the CVSC bundle at the C-terminal-most part. Note that any other contribution to the bundle would require two helices (there and back). However, we caution that no α-helix or β structure is predicted for a sizeable region of the C-terminal fragment, and we note 14 tandem repeats of the PQ pair within this region. Both features are unusual, and interpretation of the sequence and/or the structure prediction may need revisiting in light of any revisions.

Supplementary Figure 5 Comparison of pUL25 binding on the PRV and KSHV capsids.

(a) Fits of the HSV-1 pUL25 crystal structure (PDB 2F5U – Bowman, B.R. et al., J Virol. 80, 2309-17, 2006) are shown around the penton (blue) for PRV, at left, and at right for Kaposi Sarcoma herpesvirus (KSHV, EMD 6038 – Dai, X. et al., Proc Natl Acad Sci U S A 112, E649-56, 2015). The top row shows the context of the cryoEM-derived density maps, including disposition of the CVSC helical bundles in orange (PRV) and yellow (KSHV), while the bottom row shows the pUL25 model (ribbons) around schematically-represented capsomers. Note that the orientation of the penton subunit fits (PDB 1NO7 – Bowman, B.R., et al, EMBO J. 22, 757-65, 2003) reveals no significant change in orientation, whereas the pUL25 subunit fits are considerably displaced. (b) Superposition of the pUL25 fits into PRV (red) and KSHV (green) density reveals the magnitude of the displacement to be ~30°. Note that in PRV, pUL25 approaches 2 copies of the penton VP5 subunit, while the KSHV analog, pORF19, approaches only one copy. (c) Comparison of the fits reveals that the orientation of the pUL25 analogs are ~180° rotated relative to the N-terminal domain. Contacts between the KSHV protein and the capsid are therefore completely different than in PRV or HSV, despite the fold being common.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 1606 kb)

Supplementary Data Set 1

Complete western blots and SDS–PAGE used in Figure 6 (PDF 799 kb)

View of the herpesvirus capsid reconstruction

A surface view of the HSV-1 capsid density map is shown from the exterior, and as elements, including the triplex density from the exterior and interior, and a VP5 subunit from a hexon. The movie ends with a zoomed-in view showing the HK97-based fold (red) fit into the green surface of the lower domain (green). (MOV 24343 kb)

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Huet, A., Makhov, A., Huffman, J. et al. Extensive subunit contacts underpin herpesvirus capsid stability and interior-to-exterior allostery. Nat Struct Mol Biol 23, 531–539 (2016). https://doi.org/10.1038/nsmb.3212

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