Structure Analysis of the Major Capsid Proteins of Human Polyomaviruses 6 and 7 Reveals an Obstructed Sialic Acid Binding Site

Abstract

Human polyomavirus 6 (HPyV6) and HPyV7 are commonly found on human skin. We have determined the X-ray structures of their major capsid protein, VP1, at resolutions of 1.8 and 1.7 Å, respectively. In polyomaviruses, VP1 commonly determines antigenicity as well as cell-surface receptor specificity, and the protein is therefore linked to attachment, tropism, and ultimately, viral pathogenicity. The structures of HPyV6 and HPyV7 VP1 reveal uniquely elongated loops that cover the bulk of the outer virion surfaces, obstructing a groove that binds sialylated glycan receptors in many other polyomaviruses. In support of this structural observation, interactions of VP1 with ␣2,3-and ␣2,6-linked sialic acids could not be detected in solution by nuclear magnetic resonance spectroscopy. Single-cell binding studies indicate that sialylated glycans are likely not required for initial attachment to cultured human cells. Our findings establish distinct antigenic properties of HPyV6 and HPyV7 capsids and indicate that these two viruses engage nonsialylated receptors. IMPORTANCE Eleven new human polyomaviruses, including the skin viruses HPyV6 and HPyV7, have been identified during the last decade.In contrast to better-studied polyomaviruses, the routes of infection, cell tropism, and entry pathways of many of these new viruses remain largely mysterious. Our high-resolution X-ray structures of major capsid proteins VP1 from HPyV6 and from HPyV7 reveal critical differences in surface morphology from those of all other known polyomavirus structures. A groove that engages specific sialic acid-containing glycan receptors in related polyomaviruses is obstructed, and VP1 of HPyV6 and HPyV7 does not interact with sialylated compounds in solution or on cultured human cells. A comprehensive comparison with other structurally characterized polyomavirus VP1 proteins enhances our understanding of molecular determinants that underlie receptor specificity, antigenicity, and, ultimately, pathogenicity within the polyomavirus family and highlight the need for structure-based analysis to better define phylogenetic relationships within the growing polyomavirus family and perhaps also for other viruses.

Extensive genetic diversity of bat-borne polyomaviruses reveals inter-family host-switching events

“…the BC, DE, HI and EF loops, are responsible for viral antigenicity and escape mutants cluster in these regions, suggesting they represent conformational epitopes recognized by host neutralizing antibodies [65, 66]. VP1 surface loops form a unique virus-host interaction conformation that determines the host range, cellular tropism and pathogenicity which may explain the enrichment of positive selected residues within these regions [67]. The availability of annotated bat genomes in the future, as proposed by the genome consortium Bat1K [68], and annotation of the genes encoding putative entry receptors (such as, for example, the cell surface ganglioside and other sialylated glycan receptors) from within the bat families Rhinolophidae, Hipposideridae and Vespertilionidae from species previously found to harbor identical or closely related viruses would facilitate the functional characterization of the cellular receptors/attachment factors and of which amino acid residues in VP1 are required for binding and entry.…”

Polyomaviruses of the skin: integrating molecular and clinical advances in an emerging class of viruses

“…13 Interestingly, the viral protein 1 of HPyV6 and HPyV7 has shown significant differences in surface structure compared with other known polyomaviruses. 77 While the core pentamer structure is maintained, surface loops of HPyV6 and HPyV7 viral protein 1 contain obstructed sialic acid receptor sites and instead employ alternative methods of cell binding and infection. 77 The HPyV6 sT binds to the A and C subunits of PP2A, which may disable the function of PP2A.…”

“…77 While the core pentamer structure is maintained, surface loops of HPyV6 and HPyV7 viral protein 1 contain obstructed sialic acid receptor sites and instead employ alternative methods of cell binding and infection. 77 The HPyV6 sT binds to the A and C subunits of PP2A, which may disable the function of PP2A. 78 HPyV6 sTmediated inactivation of PP2A results in the hyperphosphorylation and activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase and c-Jun.…”

In Vitro and In Vivo Models for the Study of Human Polyomavirus Infection

“…To date, the cell surface receptors for KIPyV, WUPyV, HPyV6 and HPyV7 are unknown. Single-cell binding studies indicated that sialylated glycans are likely not required for viral attachment of HPyV6 and HPyV7 [45]. Structural analysis of the major capsid protein VP1 revealed that KIPyV and WUPyV VP1 possess unique structural features that suggest engagement of non-sialylated receptor types [46].…”