Human adenovirus (Ad) serotypes Ad3, Ad7, Ad11, and Ad14, as well as a recently emerged strain of Ad14 (Ad14p1), use the epithelial junction protein desmoglein 2 (DSG2) as a receptor for infection. Unlike Ad interaction with CAR and CD46, structural details for Ad binding to DSG2 are still elusive. Using an approach based on Escherichia coli expression libraries of random Ad3 and Ad14p1 fiber knob mutants, we identified amino acid residues that, when mutated individually, ablated or reduced Ad knob binding to DSG2. These residues formed three clusters inside one groove at the extreme distal end of the fiber knob. The Ad3 fiber knob mutant library was also used to identify variants with increased affinity to DSG2. We found a number of mutations within or near the EF loop of the Ad3 knob that resulted in affinities to DSG2 that were several orders of magnitude higher than those to the wild-type Ad3 knob. Crystal structure analysis of one of the mutants showed that the introduced mutations make the EF loop more flexible, which might facilitate the interaction with DSG2. Our findings have practical relevance for cancer therapy. We have recently reported that an Ad3 fiber knob-containing recombinant protein (JO-1) is able to trigger opening of junctions between epithelial cancer cells which, in turn, greatly improved the intratumoral penetration and efficacy of therapeutic agents (I. Beyer, et al., Clin. Cancer Res. 18:3340-3351, 2012; I. Beyer, et al., Cancer Res. 71:7080-7090, 2011). Here, we show that affinity-enhanced versions of JO-1 are therapeutically more potent than the parental protein in a series of cancer models.
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http://dx.doi.org/10.1128/JVI.01825-13 | DOI Listing |
Fish Physiol Biochem
February 2025
Department of Bioscience, Graduate School of Science and Technology, National University Corporation, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka, 422-8529, Japan.
Paqr9 is a gene encoding membrane progestin receptor e (mPRe), the fifth subtype of the five mPR subtypes, and is currently classified a member of the progestin and adipoQ receptor (PAQR) family, which consists of 11 genes. To elucidate the physiological functions of the mPR subtypes, we established gene knockout (KO) fish via genome editing of seven paqr genes in zebrafish and analyzed their phenotypes. The null-mutant strain of paqr9 (paqr9) that we established in this study presented reduced chorion elevation and a high percentage of abnormal embryos.
View Article and Find Full Text PDFMicroorganisms
November 2024
GuangXi Key Laboratory of Veterinary Biotechnology, GuangXi Veterinary Research Institute, Nanning 530000, China.
Fowl adenovirus serotype 4 (FAdV-4) outbreaks have caused significant economic losses in the Chinese poultry industry since 2015. The relationships among viral structural proteins in infected hosts are relatively unknown. To explore the role of different parts of the fiber-1 protein in FAdV-4-infected hosts, we truncated fiber-1 into fiber-1-Δ1 (73-205 aa) and fiber-1-Δ2 (211-412 aa), constructed pEF1α-HA-fiber-1-Δ1 and pEF1α-HA-fiber-1-Δ2 and then transfected them into leghorn male hepatocyte (LMH) cells.
View Article and Find Full Text PDFInt J Mol Sci
October 2024
Laboratory of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo 194-8543, Japan.
Numerous gene therapy drugs for cancer have received global approval, yet their efficacy against solid tumors remains inadequate. Our previous research indicated that the fiber protein, a component of the adenovirus capsid, can propagate from infected cells to neighboring cells that express the adenovirus receptor. We hypothesize that merging this fiber protein with an anti-cancer protein could enable the anti-cancer protein to disseminate around the transfected cells, presenting a novel approach to cancer gene therapy.
View Article and Find Full Text PDFVirol J
October 2024
Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany.
Front Cell Infect Microbiol
October 2024
College of Veterinary Medicine, Northwest A&F University, Yangling, China.
Background: Fowl adenovirus serotype 4 (FAdV-4) is the main pathogen of hepatitis-hydropericardium syndrome (HHS), which brings huge economic losses to the poultry industry worldwide. Fiber-1 protein plays an important role in viral infection and pathogenesis by binding directly to cellular receptors of FAdV-4. In particular, the knob domain of fiber-1 protein has been reported to induce the production of neutralizing antibodies and arouse protection against the lethal challenge of chickens with FAdV-4.
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