{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:26:24Z","timestamp":1783347984012,"version":"3.54.6"},"reference-count":41,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R35 GM122564"],"award-info":[{"award-number":["R35 GM122564"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Adeno-associated virus (AAV) is a small ssDNA satellite virus that receives wide attention due to its popularity as a safe and effective gene therapy vector. The AAV cell entry receptor (AAVR) for most serotypes is a glycoprotein containing five polycystic kidney disease (PKD) domains with which AAV interacts. AAV serotypes can be classified into three groups: those that interact primarily with PKD1, those whose interactions with PKD2 are stronger, and AAV4-like serotypes whose transduction is AAVR-independent. A phylogenetic analysis of AAVR and paralog KIAA0319 revealed AAVR amino acid variability in the region of PKD1 that is bound by AAV. We hypothesized that the substitution, in all cat-like animals, of a glutamate at a site that is an arginine (R353) in human AAVR may interfere with the binding of clade H AAVs that interact exclusively with PKD1. Analysis of PKD1 mutations, including ELISA, shows that an R353E substitution of glutamate for arginine affects the binding of the clade H AAVs that interact primarily with PKD1.<\/jats:p>","DOI":"10.3390\/v18070744","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:01:08Z","timestamp":1783346468000},"page":"744","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evolutionary Analysis Reveals a Single Amino Acid in the AAV Entry Receptor (AAVR) of Cats That Disrupts Binding of a Major Phylogenetic Group of AAVs"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9217-7174","authenticated-orcid":false,"given":"Edward E.","family":"Large","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9573-2717","authenticated-orcid":false,"given":"Isaac","family":"Mensah","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2765-5222","authenticated-orcid":false,"given":"Godfred","family":"Kumi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8525-8585","authenticated-orcid":false,"given":"Michael S.","family":"Chapman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1089\/hum.2017.048","article-title":"AAV: An Overview of Unanswered Questions","volume":"28","author":"Berns","year":"2017","journal-title":"Hum. Gene Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10405","DOI":"10.1073\/pnas.162250899","article-title":"The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy","volume":"99","author":"Xie","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1126\/science.aaw2900","article-title":"Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design","volume":"366","author":"Ogden","year":"2019","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16002","DOI":"10.1038\/mtm.2016.2","article-title":"Manufacturing of recombinant adeno-associated viral vectors for clinical trials","volume":"3","author":"Clement","year":"2016","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.tim.2021.09.005","article-title":"Adeno-associated virus (AAV) cell entry: Structural insights","volume":"30","author":"Meyer","year":"2022","journal-title":"Trends Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Large, E.E., Silveria, M.A., Zane, G.M., Weerakoon, O., and Chapman, M.S. (2021). Adeno-Associated Virus (AAV) Gene Delivery: Dissecting Molecular Interactions upon Cell Entry. Viruses, 13.","DOI":"10.3390\/v13071336"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"14018","DOI":"10.1021\/acs.chemrev.1c00936","article-title":"Cryo-electron Microscopy of Adeno-associated Virus","volume":"122","author":"Stagg","year":"2022","journal-title":"Chem. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nature16465","article-title":"An essential receptor for adeno-associated virus infection","volume":"530","author":"Pillay","year":"2016","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e00391-17","DOI":"10.1128\/JVI.00391-17","article-title":"Adeno-associated Virus (AAV) Serotypes Have Distinctive Interactions with Domains of the Cellular AAV Receptor","volume":"91","author":"Pillay","year":"2017","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/s41564-018-0356-7","article-title":"Adeno-associated virus 2 bound to its cellular receptor AAVR","volume":"4","author":"Zhang","year":"2019","journal-title":"Nat. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.1038\/s41467-019-11668-x","article-title":"Divergent engagements between adeno-associated viruses with their cellular receptor AAVR","volume":"10","author":"Zhang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e44707","DOI":"10.7554\/eLife.44707","article-title":"Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR","volume":"8","author":"Meyer","year":"2019","journal-title":"eLife"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Silveria, M.A., Large, E.E., Zane, G.M., White, T.A., and Chapman, M.S. (2020). The Structure of an AAV5-AAVR Complex at 2.5 A Resolution: Implications for Cellular Entry and Immune Neutralization of AAV Gene Therapy Vectors. Viruses, 12.","DOI":"10.3390\/v12111326"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e01484\u201322","DOI":"10.1128\/jvi.01484-22","article-title":"Cross-Species Permissivity: Structure of a Goat Adeno-Associated Virus and Its Complex with the Human Receptor AAVR","volume":"96","author":"Large","year":"2022","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.omtm.2022.05.009","article-title":"Structural basis for the neurotropic AAV9 and the engineered AAVPHP.eB recognition with cellular receptors","volume":"26","author":"Xu","year":"2022","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e02213-17","DOI":"10.1128\/JVI.02213-17","article-title":"An Alternate Route for Adeno-associated Virus (AAV) Entry Independent of AAV Receptor","volume":"92","author":"Dudek","year":"2018","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e2525865123","DOI":"10.1073\/pnas.2525865123","article-title":"Identification of CD164 as an essential entry receptor for divergent adeno-associated viruses","volume":"123","author":"Zhang","year":"2026","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e0010622","DOI":"10.1128\/jvi.00106-22","article-title":"Adeno-Associated Virus Receptor-Binding: Flexible Domains and Alternative Conformations through Cryo-Electron Tomography of Adeno-Associated Virus 2 (AAV2) and AAV5 Complexes","volume":"96","author":"Hu","year":"2022","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1089\/10430340260355347","article-title":"Insect cells as a factory to produce adeno-associated virus type 2 vectors","volume":"13","author":"Urabe","year":"2002","journal-title":"Hum. Gene Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e3513","DOI":"10.21769\/BioProtoc.3513","article-title":"Expression and Purification of Adeno-associated Virus Virus-like Particles in a Baculovirus System and AAVR Ectodomain Constructs in E. coli","volume":"10","author":"Meyer","year":"2020","journal-title":"Bio-Protocol"},{"key":"ref_21","unstructured":"Elzhov, T.V., Mullen, K.M., Spiess, A.-N., and Bolker, B. (2023). minpack.lm: R Interface to the Levenberg-Marquardt Nonlinear Least-Squares Algorithm Found in MINPACK, Plus Support for Bounds, The R Foundation. Available online: https:\/\/CRAN.R-project.org\/package=minpack.lm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1093\/bioinformatics\/btp033","article-title":"Jalview Version 2\u2014A multiple sequence alignment editor and analysis workbench","volume":"25","author":"Waterhouse","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/msb.2011.75","article-title":"Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega","volume":"7","author":"Sievers","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1093\/molbev\/msw054","article-title":"MEGA7: Molecular evolutionary genetics analysis version 7.0 for bigger datasets","volume":"33","author":"Kumar","year":"2016","journal-title":"Mol. Biol. Evol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.2108\/zsj.23.1053","article-title":"Time scale for cyclostome evolution inferred with a phylogenetic diagnosis of hagfish and lamprey cDNA sequences","volume":"23","author":"Kuraku","year":"2006","journal-title":"Zool. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Feinberg, T.E., and Mallatt, J. (2013). The evolutionary and genetic origins of consciousness in the Cambrian Period over 500 million years ago. Front. Psychol., 4.","DOI":"10.3389\/fpsyg.2013.00667"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"veaa043","DOI":"10.1093\/ve\/veaa043","article-title":"Evolution of dependoparvoviruses across geological timescales-implications for design of AAV-based gene therapy vectors","volume":"6","author":"Hildebrandt","year":"2020","journal-title":"Virus Evol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9863","DOI":"10.1128\/JVI.00828-11","article-title":"Widespread endogenization of densoviruses and parvoviruses in animal and human genomes","volume":"85","author":"Liu","year":"2011","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12458","DOI":"10.1128\/JVI.01789-10","article-title":"Sequences from ancestral single-stranded DNA viruses in vertebrate genomes: The parvoviridae and circoviridae are more than 40 to 50 million years old","volume":"84","author":"Belyi","year":"2010","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Campbell, M.A., Loncar, S., Kotin, R.M., and Gifford, R.J. (2022). Comparative analysis reveals the long-term coevolutionary history of parvoviruses and vertebrates. PLoS Biol., 20.","DOI":"10.1371\/journal.pbio.3001867"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of Coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.jsb.2012.09.006","article-title":"RELION: Implementation of a Bayesian approach to cryo-EM structure determination","volume":"180","author":"Scheres","year":"2012","journal-title":"J. Struct. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.jsb.2013.01.003","article-title":"Atomic modeling of cryo-electron microscopy reconstructions--joint refinement of model and imaging parameters","volume":"182","author":"Chapman","year":"2013","journal-title":"J. Struct. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1093\/molbev\/msx116","article-title":"TimeTree: A Resource for Timelines, Timetrees, and Divergence Times","volume":"34","author":"Kumar","year":"2017","journal-title":"Mol. Biol. Evol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Li, P., Boenzli, E., Hofmann-Lehmann, R., and Helfer-Hungerbuehler, A.K. (2019). Pre-existing antibodies to candidate gene therapy vectors (adeno-associated vector serotypes) in domestic cats. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0212811"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3140","DOI":"10.1038\/s41467-023-38721-0","article-title":"Durable contraception in the female domestic cat using viral-vectored delivery of a feline anti-M\u00fcllerian hormone transgene","volume":"14","author":"Vansandt","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1038\/sj.gt.3302087","article-title":"Adeno-associated virus vector-mediated transduction in the cat brain","volume":"10","author":"Vite","year":"2003","journal-title":"Gene Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s10162-019-00723-5","article-title":"AAV-Mediated Neurotrophin Gene Therapy Promotes Improved Survival of Cochlear Spiral Ganglion Neurons in Neonatally Deafened Cats: Comparison of AAV2-hBDNF and AAV5-hGDNF","volume":"20","author":"Leake","year":"2019","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1089\/hum.2018.028","article-title":"Virally Mediated Overexpression of Glial-Derived Neurotrophic Factor Elicits Age- and Dose-Dependent Neuronal Toxicity and Hearing Loss","volume":"30","author":"Akil","year":"2019","journal-title":"Hum. Gene Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.3390\/v13081636","article-title":"Adeno-Associated Vector-Delivered CRISPR\/SaCas9 System Reduces Feline Leukemia Virus Production In Vitro","volume":"13","author":"Shah","year":"2021","journal-title":"Viruses"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/nbt.3781","article-title":"A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear","volume":"35","author":"Landegger","year":"2017","journal-title":"Nat. Biotechnol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/7\/744\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:02:50Z","timestamp":1783346570000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/7\/744"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,4]]},"references-count":41,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["v18070744"],"URL":"https:\/\/doi.org\/10.3390\/v18070744","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,4]]}}}