Different roles of the three loops forming the adhesive interface of nectin-4 in measles virus binding and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1

Mathieu Mateo, Chanakha K. Navaratnarajah, Robin C. Willenbring, Justin W. Maroun, Ianko Iankov, Marc Lopez, Patrick L. Sinn, Roberto Cattaneo

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Many viruses utilize cell adhesion molecules of the immunoglobulin superfamily as receptors. In particular, viruses of different classes exploit nectins. The large DNA viruses, herpes simplex and pseudorabies viruses, use ubiquitous nectins 1 and 2. The negative- strand RNA virus measles virus (MeV) uses tissue-specific nectin-4, and the positive-strand RNA virus poliovirus uses nectin-like 5 (necl-5), also known as poliovirus receptor. These viruses contact the BC, C'C″, and FG loops on the upper tip of their receptor's most membrane-distal domain. This location corresponds to the newly defined canonical adhesive interface of nectins, but how viruses utilize this interface has remained unclear. Here we show that the same key residues in the BC and FG loops of nectin-4 govern binding to the MeV attachment protein hemagglutinin (H) and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1. On the other hand, residues in the C'C″ loop necessary for homo- and heterotypic interactions are dispensable for MeV-induced fusion and cell entry. Remarkably, the C'C″ loop governs dissociation of the nectin-4 and H ectodomains. We provide formal proof that H can interfere with the formation of stable nectin-1/nectin-4 heterodimers. Finally, while developing an alternative model to study MeV spread, we observed that polarized primary pig airway epithelial sheets cannot be infected. We show that a single amino acid variant in the BC loop of pig nectin-4 fully accounts for restricted MeV entry. Thus, the three loops forming the adhesive interface of nectin-4 have different roles in supporting MeV H association and dissociation and MeV-induced fusion.

Original languageEnglish (US)
Pages (from-to)14161-14171
Number of pages11
JournalJournal of Virology
Volume88
Issue number24
DOIs
StatePublished - 2014

Fingerprint

Measles virus
Virus Attachment
adhesives
Adhesives
Enterovirus C
viruses
cells
receptors
Viruses
herpes simplex
DNA viruses
swine
Suid herpesvirus 1
RNA Viruses
Homo
hemagglutinins
nectins
cell adhesion
immunoglobulins
Swine

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Different roles of the three loops forming the adhesive interface of nectin-4 in measles virus binding and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1. / Mateo, Mathieu; Navaratnarajah, Chanakha K.; Willenbring, Robin C.; Maroun, Justin W.; Iankov, Ianko; Lopez, Marc; Sinn, Patrick L.; Cattaneo, Roberto.

In: Journal of Virology, Vol. 88, No. 24, 2014, p. 14161-14171.

Research output: Contribution to journalArticle

Mateo, Mathieu ; Navaratnarajah, Chanakha K. ; Willenbring, Robin C. ; Maroun, Justin W. ; Iankov, Ianko ; Lopez, Marc ; Sinn, Patrick L. ; Cattaneo, Roberto. / Different roles of the three loops forming the adhesive interface of nectin-4 in measles virus binding and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1. In: Journal of Virology. 2014 ; Vol. 88, No. 24. pp. 14161-14171.
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AB - Many viruses utilize cell adhesion molecules of the immunoglobulin superfamily as receptors. In particular, viruses of different classes exploit nectins. The large DNA viruses, herpes simplex and pseudorabies viruses, use ubiquitous nectins 1 and 2. The negative- strand RNA virus measles virus (MeV) uses tissue-specific nectin-4, and the positive-strand RNA virus poliovirus uses nectin-like 5 (necl-5), also known as poliovirus receptor. These viruses contact the BC, C'C″, and FG loops on the upper tip of their receptor's most membrane-distal domain. This location corresponds to the newly defined canonical adhesive interface of nectins, but how viruses utilize this interface has remained unclear. Here we show that the same key residues in the BC and FG loops of nectin-4 govern binding to the MeV attachment protein hemagglutinin (H) and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1. On the other hand, residues in the C'C″ loop necessary for homo- and heterotypic interactions are dispensable for MeV-induced fusion and cell entry. Remarkably, the C'C″ loop governs dissociation of the nectin-4 and H ectodomains. We provide formal proof that H can interfere with the formation of stable nectin-1/nectin-4 heterodimers. Finally, while developing an alternative model to study MeV spread, we observed that polarized primary pig airway epithelial sheets cannot be infected. We show that a single amino acid variant in the BC loop of pig nectin-4 fully accounts for restricted MeV entry. Thus, the three loops forming the adhesive interface of nectin-4 have different roles in supporting MeV H association and dissociation and MeV-induced fusion.

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