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Structural insights into the interaction between adenovirus C5 hexon and human lactoferrin
Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, Prague, Czech Republic.
Swedish Veterinary Agency, Uppsala, Sweden.
VIB-VUB Center for Structural Biology, Flemish Institute of Biotechnology (VIB), Brussels, Belgium; Jean Jeener NMR Centre, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, Prague, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic.
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2024 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 98, no 3, article id e01576-23Article in journal (Refereed) Published
Abstract [en]

Adenovirus (AdV) infection of the respiratory epithelium is common but poorly understood. Human AdV species C types, such as HAdV-C5, utilize the Coxsackieadenovirus receptor (CAR) for attachment and subsequently integrins for entry. CAR and integrins are however located deep within the tight junctions in the mucosa where they would not be easily accessible. Recently, a model for CAR-independent AdV entry was proposed. In this model, human lactoferrin (hLF), an innate immune protein, aids the viral uptake into epithelial cells by mediating interactions between the major capsid protein, hexon, and yet unknown host cellular receptor(s). However, a detailed understanding of the molecular interactions driving this mechanism is lacking. Here, we present a new cryo-EM structure of HAdV-5C hexon at high resolution alongside a hybrid structure of HAdV-5C hexon complexed with human lactoferrin (hLF). These structures reveal the molecular determinants of the interaction between hLF and HAdV-C5 hexon. hLF engages hexon primarily via its N-terminal lactoferricin (Lfcin) region, interacting with hexon’s hypervariable region 1 (HVR-1). Mutational analyses pinpoint critical Lfcin contacts and also identify additional regions within hLF that critically contribute to hexon binding. Our study sheds more light on the intricate mechanism by which HAdV-C5 utilizes soluble hLF/Lfcin for cellular entry. These findings hold promise for advancing gene therapy applications and inform vaccine development.

Place, publisher, year, edition, pages
2024. Vol. 98, no 3, article id e01576-23
Keywords [en]
adenovirus, cryo-EM, immune evasion, lactoferrin, viral entry
National Category
Microbiology in the medical area Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-222882DOI: 10.1128/jvi.01576-23ISI: 001158715300002PubMedID: 38323814Scopus ID: 2-s2.0-85188480462OAI: oai:DiVA.org:umu-222882DiVA, id: diva2:1851023
Funder
EU, Horizon 2020European Regional Development Fund (ERDF)EU, Horizon 2020, ERC StG-2017 759661Available from: 2024-04-12 Created: 2024-04-12 Last updated: 2024-04-12Bibliographically approved

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Danskog, KatarinaArnberg, Niklas

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