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Structural Insights into the Interaction Between Adenovirus 5C Hexon and Human Lactoferrin

ABSTRACT: Adenovirus (AdV) infection of the respiratory epithelium is common but poorly understood. Human infective species C AdVs, such as HAdV-C5, utilise the Coxsackie-Adenovirus 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, Lactoferrin (LF), 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). Yet, a detailed understanding of the molecular interactions driving this mechanism is lacking. Here, we present a novel cryo-EM structure of HAd-5C hexon at high resolution alongside a hybrid structure of human lactoferrin (hLF) complexed with HAdV-5C hexon. 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 but 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 utilises soluble hLF/Lfcin for cellular entry. These findings hold promise for advancing gene therapy applications and inform vaccine development.

INSTRUMENT(S): maXis

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Whole Body

SUBMITTER: Petr Pompach

LAB HEAD: Sebastian Zoll

PROVIDER: PXD045900 | Pride | 2024-02-03

REPOSITORIES: Pride

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			Action	DRS
	Hex_LF_500x.zhrm	Other
	Hex_LF_500x_A1_1_1197.mgf	Mgf
	rLF_Adv5.fasta	Fasta

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