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

doi:10.1128/JVI.02379-14

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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

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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 and Roberto Cattaneo

Journal of virology, Vol.88(24), pp.14161-14171

12/2014

DOI: 10.1128/JVI.02379-14

PMCID: PMC4249131

PMID: 25275122

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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. Different viruses utilize nectins as receptors. Nectins are immunoglobulin superfamily glycoproteins that mediate cell-cell adhesion in vertebrate tissues. They interact through an adhesive interface located at the top of their membrane-distal domain. How viruses utilize the three loops forming this interface has remained unclear. We demonstrate that while nectin-nectin interactions require residues in all three loops, the association of nectin-4 with the measles virus hemagglutinin requires only the BC and FG loops. However, we discovered that residues in the C'C" loop modulate the dissociation of nectin-4 from the viral hemagglutinin. Analogous mechanisms may support cell entry of other viruses that utilize nectins or other cell adhesion molecules of the immunoglobulin superfamily as receptors.

Amino Acid Sequence

Cell Line

Hemagglutinins, Viral - metabolism

Receptors, Virus - metabolism

Humans

Protein Multimerization

Molecular Sequence Data

Cell Adhesion Molecules - metabolism

Nectins

Virus Internalization

Sequence Alignment

Animals

Virus Attachment

Measles virus - physiology

Details

Title: Subtitle: 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
Creators: Mathieu Mateo - Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
Chanakha K Navaratnarajah - Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
Robin C Willenbring - Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA Virology and Gene Therapy track, Mayo Graduate School, Rochester, Minnesota, USA
Justin W Maroun - Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA Virology and Gene Therapy track, Mayo Graduate School, Rochester, Minnesota, USA
Ianko Iankov - Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
Marc Lopez - INSERM, UMR1068/CRCM, Institut Paoli-Calmettes and University of Aix-Marseille, Marseille, France
Patrick L Sinn - Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA
Roberto Cattaneo - Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA Virology and Gene Therapy track, Mayo Graduate School, Rochester, Minnesota, USA cattaneo.roberto@mayo.edu
Resource Type: Journal article
Publication Details: Journal of virology, Vol.88(24), pp.14161-14171
DOI: 10.1128/JVI.02379-14
PMID: 25275122
PMCID: PMC4249131
NLM abbreviation: J Virol
ISSN: 0022-538X
eISSN: 1098-5514
Grant note: R01 HL105821 / NHLBI NIH HHS R01 HL-105821 / NHLBI NIH HHS P30 DK054759 / NIDDK NIH HHS R01 AI063476 / NIAID NIH HHS
Language: English
Date published: 12/2014
Academic Unit: Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics
Record Identifier: 9984093455302771

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