VP1 residues around the five-fold axis of enterovirus A71 mediate heparan sulfate interaction
Enterovirus A71 (EV-A71) is a neurotropic enterovirus that uses heparan sulfate as an attachment receptor. The molecular determinants of EV-A71-heparan sulfate interaction are unknown. With In silico heparin docking and mutagenesis of all possible lysine residues in VP1, we identified that K162, K24...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Published: |
Elsevier
2017
|
| Subjects: |
| _version_ | 1796960596369866752 |
|---|---|
| author | Tan, C.W. Sam, I.C. Lee, V.S. Wong, H.V. Chan, Y.F. |
| author_facet | Tan, C.W. Sam, I.C. Lee, V.S. Wong, H.V. Chan, Y.F. |
| author_sort | Tan, C.W. |
| collection | UM |
| description | Enterovirus A71 (EV-A71) is a neurotropic enterovirus that uses heparan sulfate as an attachment receptor. The molecular determinants of EV-A71-heparan sulfate interaction are unknown. With In silico heparin docking and mutagenesis of all possible lysine residues in VP1, we identified that K162, K242 and K244 are responsible for heparin interaction and inhibition. EV-A71 mutants with K242A and K244A rapidly acquired compensatory mutations, T100K or E98A, and Q145R-T237N respectively, which restored the heparin-binding phenotype. Both VP1-98 and VP1-145 modulates heparin binding. Heparin-binding phenotype was completely abolished with VP1-E98-E145, but was restored by an E98K or E145Q substitution. During cell culture adaptation, EV-A71 rapidly acquired K98 or Q/G145 to restore the heparin-binding phenotype. Together with next-generation sequencing analysis, our results implied that EV-A71 has high genetic plasticity by modulating positively-charged residues at the five-fold axis during in vitro heparin adaptation. Our finding has impact on EV-A71 vaccine production, evolutionary studies and pathogenesis. |
| first_indexed | 2024-03-06T05:47:00Z |
| format | Article |
| id | um.eprints-19012 |
| institution | Universiti Malaya |
| last_indexed | 2024-03-06T05:47:00Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | um.eprints-190122018-08-17T01:16:31Z http://eprints.um.edu.my/19012/ VP1 residues around the five-fold axis of enterovirus A71 mediate heparan sulfate interaction Tan, C.W. Sam, I.C. Lee, V.S. Wong, H.V. Chan, Y.F. QD Chemistry R Medicine Enterovirus A71 (EV-A71) is a neurotropic enterovirus that uses heparan sulfate as an attachment receptor. The molecular determinants of EV-A71-heparan sulfate interaction are unknown. With In silico heparin docking and mutagenesis of all possible lysine residues in VP1, we identified that K162, K242 and K244 are responsible for heparin interaction and inhibition. EV-A71 mutants with K242A and K244A rapidly acquired compensatory mutations, T100K or E98A, and Q145R-T237N respectively, which restored the heparin-binding phenotype. Both VP1-98 and VP1-145 modulates heparin binding. Heparin-binding phenotype was completely abolished with VP1-E98-E145, but was restored by an E98K or E145Q substitution. During cell culture adaptation, EV-A71 rapidly acquired K98 or Q/G145 to restore the heparin-binding phenotype. Together with next-generation sequencing analysis, our results implied that EV-A71 has high genetic plasticity by modulating positively-charged residues at the five-fold axis during in vitro heparin adaptation. Our finding has impact on EV-A71 vaccine production, evolutionary studies and pathogenesis. Elsevier 2017 Article PeerReviewed Tan, C.W. and Sam, I.C. and Lee, V.S. and Wong, H.V. and Chan, Y.F. (2017) VP1 residues around the five-fold axis of enterovirus A71 mediate heparan sulfate interaction. Virology, 501. pp. 79-87. ISSN 0042-6822, DOI https://doi.org/10.1016/j.virol.2016.11.009 <https://doi.org/10.1016/j.virol.2016.11.009>. http://dx.doi.org/10.1016/j.virol.2016.11.009 doi:10.1016/j.virol.2016.11.009 |
| spellingShingle | QD Chemistry R Medicine Tan, C.W. Sam, I.C. Lee, V.S. Wong, H.V. Chan, Y.F. VP1 residues around the five-fold axis of enterovirus A71 mediate heparan sulfate interaction |
| title | VP1 residues around the five-fold axis of enterovirus A71 mediate heparan sulfate interaction |
| title_full | VP1 residues around the five-fold axis of enterovirus A71 mediate heparan sulfate interaction |
| title_fullStr | VP1 residues around the five-fold axis of enterovirus A71 mediate heparan sulfate interaction |
| title_full_unstemmed | VP1 residues around the five-fold axis of enterovirus A71 mediate heparan sulfate interaction |
| title_short | VP1 residues around the five-fold axis of enterovirus A71 mediate heparan sulfate interaction |
| title_sort | vp1 residues around the five fold axis of enterovirus a71 mediate heparan sulfate interaction |
| topic | QD Chemistry R Medicine |
| work_keys_str_mv | AT tancw vp1residuesaroundthefivefoldaxisofenterovirusa71mediateheparansulfateinteraction AT samic vp1residuesaroundthefivefoldaxisofenterovirusa71mediateheparansulfateinteraction AT leevs vp1residuesaroundthefivefoldaxisofenterovirusa71mediateheparansulfateinteraction AT wonghv vp1residuesaroundthefivefoldaxisofenterovirusa71mediateheparansulfateinteraction AT chanyf vp1residuesaroundthefivefoldaxisofenterovirusa71mediateheparansulfateinteraction |