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Sialic acid-dependent cell entry of human enterovirus D68.

Liu Y, Sheng J, Baggen J, Meng G, Xiao C, Thibaut HJ, van Kuppeveld FJ, Rossmann MG - Nat Commun (2015)

Bottom Line: Human enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat.Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells.Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the 'canyon' on the virus surface.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Hockmeyer Hall of Structural Biology, 240 South Martin Jischke Drive, Purdue University, West Lafayette, Indiana 47907, USA.

ABSTRACT
Human enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat. Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells. Here we demonstrate that cell surface sialic acid is essential for EV-D68 to bind to and infect susceptible cells. Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the 'canyon' on the virus surface. The sialic acid receptor induces a cascade of conformational changes in the virus to eject a fatty-acid-like molecule that regulates the stability of the virus. Thus, virus binding to a sialic acid receptor and to immunoglobulin-like receptors used by most other enteroviruses share a conserved mechanism for priming viral uncoating and facilitating cell entry.

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Competition between the sialic acid receptor and the pocket factor.(a) The conformational changes of the virus when sialylated receptor analogues bind the virus and eject the pocket factor. Amino acids in the native and in the receptor bound structures are shown in yellow and cyan, respectively. A water molecule is shown as a red sphere. Dash lines represent polar interactions. Red arrows indicate movements of the four loops. (b) Enlarged component of marked region in (a) shown in a slightly different orientation. (c) Preincubation of EV-D68 with pleconaril inhibits viral attachment onto non-treated HELF cells. Data are represented as mean±s.d. Experiments were done in triplicate.
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f4: Competition between the sialic acid receptor and the pocket factor.(a) The conformational changes of the virus when sialylated receptor analogues bind the virus and eject the pocket factor. Amino acids in the native and in the receptor bound structures are shown in yellow and cyan, respectively. A water molecule is shown as a red sphere. Dash lines represent polar interactions. Red arrows indicate movements of the four loops. (b) Enlarged component of marked region in (a) shown in a slightly different orientation. (c) Preincubation of EV-D68 with pleconaril inhibits viral attachment onto non-treated HELF cells. Data are represented as mean±s.d. Experiments were done in triplicate.

Mentions: The r.m.s.d. between all the equivalent atoms of the EV-D68 native structure and the EV-D68 bound with any of the three receptor analogues is about 0.4 Å (Supplementary Table 4). Nearly all main chain atoms that were displaced by more than four r.m.s.d. were in the loops that form the connecting region between the sialic acid binding site and the VP1 hydrophobic pocket. The same conformational changes occurred in each of the three complexes. The conformational changes included the VP1 GH loop located at the boundary between the VP1 hydrophobic pocket and the canyon. Similar changes in the VP1 GH loop occur when CD155 binds to poliovirus14. In particular, the Cα atom of residue Ile1217 moves 2.2 Å into the pocket (Fig. 3). This results in a conformation of the VP1 GH loop much like that in the rhinovirus 14 structure where no pocket factor is present6. Thus binding of sialylated receptor analogues onto EV-D68 causes a partial collapse of the pocket, leading to the displacement of the pocket factor (Fig. 4). However, in these sialylated receptor analogue bound structures, the VP4 density is still present and the particle size is not altered, indicating that sialylated glycan binding of EV-D68 at room temperature represents an initial event of the viral entry process. In contrast to the conformational changes that occur when a sialic acid receptor binds into the canyon, binding of glycan receptors to other binding sites (Supplementary Table 5) on picornaviruses do not cause further conformational changes.


Sialic acid-dependent cell entry of human enterovirus D68.

Liu Y, Sheng J, Baggen J, Meng G, Xiao C, Thibaut HJ, van Kuppeveld FJ, Rossmann MG - Nat Commun (2015)

Competition between the sialic acid receptor and the pocket factor.(a) The conformational changes of the virus when sialylated receptor analogues bind the virus and eject the pocket factor. Amino acids in the native and in the receptor bound structures are shown in yellow and cyan, respectively. A water molecule is shown as a red sphere. Dash lines represent polar interactions. Red arrows indicate movements of the four loops. (b) Enlarged component of marked region in (a) shown in a slightly different orientation. (c) Preincubation of EV-D68 with pleconaril inhibits viral attachment onto non-treated HELF cells. Data are represented as mean±s.d. Experiments were done in triplicate.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4660200&req=5

f4: Competition between the sialic acid receptor and the pocket factor.(a) The conformational changes of the virus when sialylated receptor analogues bind the virus and eject the pocket factor. Amino acids in the native and in the receptor bound structures are shown in yellow and cyan, respectively. A water molecule is shown as a red sphere. Dash lines represent polar interactions. Red arrows indicate movements of the four loops. (b) Enlarged component of marked region in (a) shown in a slightly different orientation. (c) Preincubation of EV-D68 with pleconaril inhibits viral attachment onto non-treated HELF cells. Data are represented as mean±s.d. Experiments were done in triplicate.
Mentions: The r.m.s.d. between all the equivalent atoms of the EV-D68 native structure and the EV-D68 bound with any of the three receptor analogues is about 0.4 Å (Supplementary Table 4). Nearly all main chain atoms that were displaced by more than four r.m.s.d. were in the loops that form the connecting region between the sialic acid binding site and the VP1 hydrophobic pocket. The same conformational changes occurred in each of the three complexes. The conformational changes included the VP1 GH loop located at the boundary between the VP1 hydrophobic pocket and the canyon. Similar changes in the VP1 GH loop occur when CD155 binds to poliovirus14. In particular, the Cα atom of residue Ile1217 moves 2.2 Å into the pocket (Fig. 3). This results in a conformation of the VP1 GH loop much like that in the rhinovirus 14 structure where no pocket factor is present6. Thus binding of sialylated receptor analogues onto EV-D68 causes a partial collapse of the pocket, leading to the displacement of the pocket factor (Fig. 4). However, in these sialylated receptor analogue bound structures, the VP4 density is still present and the particle size is not altered, indicating that sialylated glycan binding of EV-D68 at room temperature represents an initial event of the viral entry process. In contrast to the conformational changes that occur when a sialic acid receptor binds into the canyon, binding of glycan receptors to other binding sites (Supplementary Table 5) on picornaviruses do not cause further conformational changes.

Bottom Line: Human enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat.Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells.Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the 'canyon' on the virus surface.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Hockmeyer Hall of Structural Biology, 240 South Martin Jischke Drive, Purdue University, West Lafayette, Indiana 47907, USA.

ABSTRACT
Human enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat. Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells. Here we demonstrate that cell surface sialic acid is essential for EV-D68 to bind to and infect susceptible cells. Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the 'canyon' on the virus surface. The sialic acid receptor induces a cascade of conformational changes in the virus to eject a fatty-acid-like molecule that regulates the stability of the virus. Thus, virus binding to a sialic acid receptor and to immunoglobulin-like receptors used by most other enteroviruses share a conserved mechanism for priming viral uncoating and facilitating cell entry.

Show MeSH
Related in: MedlinePlus