title: Genetic and structural analysis of polyomavirus BK T-antigens reveal a higher density of mutations at inter-domain and hexamerization regions, regardless the status of infection.
abstract: Polyomavirus BK (BKPyV) T-antigens (large and small tumor antigens, or Lt-ag and st-ag, respectively), control key aspects of viral replication and are able to regulate cell cycle, promoting cell proliferation. However, the structural effects of genetic mutations on T-antigens are poorly investigated. In this study, 214 sequences of T-antigens from individuals with different BKPyV infections (16 renal transplant with nephropathy; 78 asymptomatic renal transplant; 24 hematopoietic stem cell transplant with hemorrhagic cystitis; 96 healthy non-transplant), were analyzed from the genetic and structural standpoints. We found a high concentration of non-synonymous mutations at inter-domains and hexamerization regions of both proteins, being five of them under positive selection in the Lt-ag but none in the st-ag. The in silico analysis indicated that two mutations, located at positions 164 in the st-ag and 592 in the Lt-ag, would significantly affect the interaction with PP2A and p53 cell targets, respectively, although they were not associated to a specific clinical status. No mutations were detected on the J-domains or at the ATPase motif. In sum, the profile of the mutations found seem not to be associated to increased morbidity. This is the first work to analyze structural modifications on T-antigens in different BKPyV infections, and managed to map conserved and variable regions of the T-antigens, which will be helpful for the study of new antiviral drugs.
authors.affiliation: Department of Microbiology and Parasitology, Universidade Federal Fluminense, Niterói, Brazil.
authors.forename: Kethellin M
authors.initials: KM
authors.lastname: Cardoso
authors.affiliation: Department of Pharmaceutical Biotechnology, Universidade Federal do Rio do Janeiro, Rio de Janeiro, Brazil.
authors.forename: Nuria C
authors.initials: NC
authors.lastname: Diaz
authors.affiliation: Department of Preventive Medicine, Universidade Federal do Rio do Janeiro, Rio de Janeiro, Brazil.
authors.forename: Maria Angelica A M
authors.initials: MA
authors.lastname: Guimarães
authors.affiliation: Department of Preventive Medicine, Universidade Federal do Rio do Janeiro, Rio de Janeiro, Brazil.
authors.forename: Mariano G
authors.initials: MG
authors.lastname: Zalis
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milano, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Delbue
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milano, Milan, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Ferrante
authors.affiliation: Department of Microbiology and Parasitology, Universidade Federal Fluminense, Niterói, Brazil.
authors.forename: Rafael B
authors.initials: RB
authors.lastname: Varella
mesh_terms: D000957:Antigens, Viral, Tumor / Q000235:genetics*; D001739:BK Virus / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D027601:Polyomavirus Infections / Q000821:virology*; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D014412:Tumor Virus Infections / Q000821:virology*
chemical_list: D000957:Antigens, Viral, Tumor; D004279:DNA, Viral
keywords: BKPyV; in silico; large T-antigen; mutation; small T-antigen