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Yang YC, Hearing P, & Rundell K (1979). Cellular proteins associated with simian virus 40 early gene products in newly infected cells. Journal of Virology, 32(1), 147–154. [PubMed: 232167]

Yu G, Greninger AL, Isa P, Phan TG, Martínez MA, de la Luz Sanchez M, Chiu CY (2012). Discovery of a novel polyomavirus in acute diarrheal samples from children. PLOS One, 7(11), e49449. [PubMed: 23166671]

Zerrahn J, Knippschild U, Winkler T, & Deppert W (1993). Independent expression of the transforming amino-terminal domain of SV40 large I antigen from an alternatively spliced third SV40 early mRNA. EMBO Journal, 12(12), 4739–4746. [PubMed: 8223482]

Zhang J, Li S, Li L, Li M, Guo C, Yao J, & Mi S (2015). Exosome and exosomal microRNA: Trafficking, sorting, and function. Genomics, Proteomics & Bioinformatics, 13(1), 17–24.

Zhao LJ, Wang L, Mukherjee S, & Narayan O (1994a). Biochemical mechanism of HIV-1 Vpr function. Oligomerization mediated by the N-terminal domain. Journal of Biological Chemistry, 269(51), 32131–32137. [PubMed: 7798208]

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<figure><img src="image_3.png" /><figcaption>FIGURE 1.</figcaption></figure>

Circular map of JC virus. (a) The genome of JC virus contains three functional regions. 1, Control region, which contains the origin of DNA replication and promoter-enhancer elements for early and late genes. 2, Early coding region, which encodes LT-Ag, Sm t-Ag, T'proteins (T'165, T'135, and T'136) due to cis-alternative splicing of the early pre-mRNA. 3, Late coding region which encodes capsid proteins (VP1, VP2, and VP3) and a regulatory protein, agnoprotein. In addition, late region also encodes two additional proteins ORF1 and ORF2 due to trans-splicing of the late pre-mRNA. (b) The coding regions of ORF1 and ORF2 are created by insertion of a partial coding region of VP1 in between agnoprotein and VP2 coding regions. A schematic demonstration of the mechanism of the creation of ORF1 and ORF2, open reading frames (see text for details; Saribas, DeVoto, et al., 2018). LT-Ag: large tumor antigen; mRNA: messenger RNA; Sm t-Ag: small tumor antigen [Color figure can be viewed at wileyonlinelibrary.com]
<figure><img src="image_3.png" /></figure>

FIGURE 1.

Circular map of JC virus. (a) The genome of JC virus contains three functional regions. 1, Control region, which contains the origin of DNA replication and promoter-enhancer elements for early and late genes. 2, Early coding region, which encodes LT-Ag, Sm t-Ag, T'proteins (T'165, T'135, and T'136) due to cis-alternative splicing of the early pre-mRNA. 3, Late coding region which encodes capsid proteins (VP1, VP2, and VP3) and a regulatory protein, agnoprotein. In addition, late region also encodes two additional proteins ORF1 and ORF2 due to trans-splicing of the late pre-mRNA. (b) The coding regions of ORF1 and ORF2 are created by insertion of a partial coding region of VP1 in between agnoprotein and VP2 coding regions. A schematic demonstration of the mechanism of the creation of ORF1 and ORF2, open reading frames (see text for details; Saribas, DeVoto, et al., 2018). LT-Ag: large tumor antigen; mRNA: messenger RNA; Sm t-Ag: small tumor antigen [Color figure can be viewed at wileyonlinelibrary.com]
<figure><img src="image_4.png" /><figcaption>FIGURE 2.</figcaption></figure>

Predicted and validated functional motifs of JCV agnoprotein. (a) Phosphorylation of Ser7, Ser11, and Thr21 was previously demonstrated (Johannessen et al., 2008; Sariyer et al., 2006). The website, https://wolfpsort.hgc.jp/ was used to predict the functional motif or domains. (b) For prediction of mitochondrial targeting sequences, the following website was used: http://mitf.cbrc.jp/MitoFates/cgi-bin/top.cgi. JCV: JC virus, ER: Endoplasmic reticulum [Color figure can be viewed at wileyonlinelibrary.com]
<figure><img src="image_4.png" /><figcaption>FIGURE 2.</figcaption></figure>

Predicted and validated functional motifs of JCV agnoprotein. (a) Phosphorylation of Ser7, Ser11, and Thr21 was previously demonstrated (Johannessen et al., 2008; Sariyer et al., 2006). The website, https://wolfpsort.hgc.jp/ was used to predict the functional motif or domains. (b) For prediction of mitochondrial targeting sequences, the following website was used: http://mitf.cbrc.jp/MitoFates/cgi-bin/top.cgi. JCV: JC virus, ER: Endoplasmic reticulum [Color figure can be viewed at wileyonlinelibrary.com]
<figure><img src="image_5.png" /><figcaption>FIGURE 3.</figcaption></figure>

The 3D structure of the full-length JC virus agnoprotein was recently resolved by NMR (Coric et al., 2017). According to this 3D structure, agnoprotein contains a minor and a major α-helix located at amino acid position Leu6-Lys13 and Arg24-Phe39, respectively. The rest of the protein adopts an intrinsically unstructured conformation (Met1-Gln5, Val14-Lys23, and Cyt40-Thr71). 3D: three dimensional; NMR: nuclear magnetic resonance [Color figure can be viewed at wileyonlinelibrary.com]
<figure><img src="image_5.png" /><figcaption>FIGURE 3.</figcaption></figure>

The 3D structure of the full-length JC virus agnoprotein was recently resolved by NMR (Coric et al., 2017). According to this 3D structure, agnoprotein contains a minor and a major α-helix located at amino acid position Leu6-Lys13 and Arg24-Phe39, respectively. The rest of the protein adopts an intrinsically unstructured conformation (Met1-Gln5, Val14-Lys23, and Cyt40-Thr71). 3D: three dimensional; NMR: nuclear magnetic resonance [Color figure can be viewed at wileyonlinelibrary.com]
<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /><figcaption>FIGURE 4.</figcaption></figure>

Theoretical dimer formation by agnoprotein through the hydrophobic face I and II, both of which are located at the major α-helix domain. (a, b) The first homodimer is formed through the interface of Leu29, Leu32 and Leu36 residues located at the hydrophobic face I and is illustrated by a radial (a) and axial (b) view. The side chains of the residues are represented in a stick conformation. The backbone of each α-helix is represented in a ribbon representation and colored in purple. Amino acids Leu29, Leu32, and Leu36 located at the interface are colored in yellow and aromatic residues Phe31, Phe35, and Phe39 forming an aromatic cluster are colored in green. (c, d) The second homodimer structure is formed through the interface of Ile30, Leu33, and Leu37, which are located on the hydrophobic face II and is also represented in a radial (c) and axial (d) view. The backbone of the antiparallel α-helices is illustrated in a ribbon representation and colored in purple. The hydrophobic residues Ile30, Leu33, and Leu37 forming the interface are illustrated in a stick representation and colored in orange. Phenylalanine residues, Phe31, Phe35, and Phe39, forming an aromatic cluster are colored in green. The data used to build each homodimer
<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /><figcaption>FIGURE 4.</figcaption></figure>

Theoretical dimer formation by agnoprotein through the hydrophobic face I and II, both of which are located at the major α-helix domain. (a, b) The first homodimer is formed through the interface of Leu29, Leu32 and Leu36 residues located at the hydrophobic face I and is illustrated by a radial (a) and axial (b) view. The side chains of the residues are represented in a stick conformation. The backbone of each α-helix is represented in a ribbon representation and colored in purple. Amino acids Leu29, Leu32, and Leu36 located at the interface are colored in yellow and aromatic residues Phe31, Phe35, and Phe39 forming an aromatic cluster are colored in green. (c, d) The second homodimer structure is formed through the interface of Ile30, Leu33, and Leu37, which are located on the hydrophobic face II and is also represented in a radial (c) and axial (d) view. The backbone of the antiparallel α-helices is illustrated in a ribbon representation and colored in purple. The hydrophobic residues Ile30, Leu33, and Leu37 forming the interface are illustrated in a stick representation and colored in orange. Phenylalanine residues, Phe31, Phe35, and Phe39, forming an aromatic cluster are colored in green. The data used to build each homodimer
structure of agnoprotein are the same as the one used to build the homodimer structure for the short fragment of agnoprotein (aa 17–52; Coric et al., 2014). The structure of each theoretical dimer was calculated using simulated annealing with restrained molecular dynamics and energy minimization with the X-PLOR program (Arkin, Sukharev, Blount, Kung, & Brunger, 1998; Fleming et al., 1998) implemented with a total of 453 distance restraints for dimer A (a) and 447 distance restraints for dimer C (c). To build each dimer, 232 intermolecular nuclear overhauser effect (NOE)-derived distances were unambiguously defined to build dimer A with interface L29, L32, and L36 (a) and 68 for dimer C with interface I30, L33, and L37 (c) respectively [Color figure can be viewed at wileyonlinelibrary.com]
structure of agnoprotein are the same as the one used to build the homodimer structure for the short fragment of agnoprotein (aa 17–52; Coric et al., 2014). The structure of each theoretical dimer was calculated using simulated annealing with restrained molecular dynamics and energy minimization with the X-PLOR program (Arkin, Sukharev, Blount, Kung, & Brunger, 1998; Fleming et al., 1998) implemented with a total of 453 distance restraints for dimer A (a) and 447 distance restraints for dimer C (c). To build each dimer, 232 intermolecular nuclear overhauser effect (NOE)-derived distances were unambiguously defined to build dimer A with interface L29, L32, and L36 (a) and 68 for dimer C with interface I30, L33, and L37 (c) respectively [Color figure can be viewed at wileyonlinelibrary.com]
<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /><figcaption>FIGURE 5.</figcaption></figure>

Surface fill-in representation of the theoretical homodimeric structure of agnoprotein formed through the interface Leu29, Leu32, and Leu36. Two opposite faces with equivalent properties are shown colored according their hydrophobic properties. (a) The first hydrophobic face is constituted of the hydrophobic residues Leu29, Ile30, Leu33 and Leu37.

(b) The opposite face of the dimer is also constituted of the hydrophobic residues Ala25, Ile28, Phe31, Leu32, Phe35, Leu36, and Phe39. (c) The surface fill-in representation of the theoretical dimeric structure of agnoprotein formed through the interface of Ile30, Leu33, and Leu37. The surface is colored according to the hydrophobic properties of the amino acids. Two opposite faces with different properties can be distinguished. The first one is constituted of the hydrophilic residues Lys23, Arg24, Gln26, Arg27, Glu34, and Asp38 (c)
<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /><figcaption>FIGURE 5.</figcaption></figure>

Surface fill-in representation of the theoretical homodimeric structure of agnoprotein formed through the interface Leu29, Leu32, and Leu36. Two opposite faces with equivalent properties are shown colored according their hydrophobic properties. (a) The first hydrophobic face is constituted of the hydrophobic residues Leu29, Ile30, Leu33 and Leu37.

(b) The opposite face of the dimer is also constituted of the hydrophobic residues Ala25, Ile28, Phe31, Leu32, Phe35, Leu36, and Phe39. (c) The surface fill-in representation of the theoretical dimeric structure of agnoprotein formed through the interface of Ile30, Leu33, and Leu37. The surface is colored according to the hydrophobic properties of the amino acids. Two opposite faces with different properties can be distinguished. The first one is constituted of the hydrophilic residues Lys23, Arg24, Gln26, Arg27, Glu34, and Asp38 (c)
while the opposite one is also composed of more hydrophobic residues Leu29, Ile30, Phe31, Leu32, Leu33, Phe35, Leu36, Leu37, and Phe39; and forms a relatively larger hydrophobic face (d) [Color figure can be viewed at wileyonlinelibrary.com]
while the opposite one is also composed of more hydrophobic residues Leu29, Ile30, Phe31, Leu32, Leu33, Phe35, Leu36, Leu37, and Phe39; and forms a relatively larger hydrophobic face (d) [Color figure can be viewed at wileyonlinelibrary.com]
<figure><img src="image_14.png" /><figcaption>FIGURE 6.</figcaption></figure>

Hydrophilic residues located on the major α-helix domain play important roles in release of agnoprotein. Three-dimensional structure of the full-length agnoprotein is illustrated in a “surface fill-in” representation. The hydrophilic residues located on the hydrophilic face of the major α-helix domain of agnoprotein, including Lys22, Lys23, Glu34, and Asp38; and an aromatic residue (Phe31), which is adjacent to this hydrophilic surface were determined to be critical for the release of agnoprotein from agnoprotein-positive cells (Saribas, White, et al., 2018). Amino acid residues involved in agnoprotein release are encased in boxes and named. Note that Lys23, Lys23, Phe31, and Glu34 are all conversed between JCV, BKV, and SV40 agnoproteins. JCV Asp38 is substituted for Glu and Gln for BKV and SV40 agnoproteins, respectively, at the same position (Saribas, White, et al., 2018). BKV: BK virus; JCV: JC virus; SV40: simian virus 40 [Color figure can be viewed at wileyonlinelibrary.com]
<figure><img src="image_14.png" /><figcaption>FIGURE 6.</figcaption></figure>

Hydrophilic residues located on the major α-helix domain play important roles in release of agnoprotein. Three-dimensional structure of the full-length agnoprotein is illustrated in a “surface fill-in” representation. The hydrophilic residues located on the hydrophilic face of the major α-helix domain of agnoprotein, including Lys22, Lys23, Glu34, and Asp38; and an aromatic residue (Phe31), which is adjacent to this hydrophilic surface were determined to be critical for the release of agnoprotein from agnoprotein-positive cells (Saribas, White, et al., 2018). Amino acid residues involved in agnoprotein release are encased in boxes and named. Note that Lys23, Lys23, Phe31, and Glu34 are all conversed between JCV, BKV, and SV40 agnoproteins. JCV Asp38 is substituted for Glu and Gln for BKV and SV40 agnoproteins, respectively, at the same position (Saribas, White, et al., 2018). BKV: BK virus; JCV: JC virus; SV40: simian virus 40 [Color figure can be viewed at wileyonlinelibrary.com]
Currently known human polyomaviruses

<table><thead><tr><th>Full names</th><th>Abbreviations</th><th>Source of isolation</th><th>Time of discovery</th><th>Associated disease</th></tr></thead><tbody><tr><td>JC virus</td><td>JCPyV</td><td>Brain, PML patient</td><td>Padgett et al. (1971)</td><td>Progressive multifocal leukoencephalopathy</td></tr><tr><td>BK virus</td><td>BKPyV</td><td>Urine, kidney transplant recipient</td><td>Gardner et al. (1971)</td><td>BK virus-associated nephropathy, Hemorrhagic cystitis</td></tr><tr><td>Karolinska Institute polyomavirus</td><td>KIPyV</td><td>Nasopharyngeal tissue</td><td>Allander et al. (2007)</td><td>Respiratory disease</td></tr><tr><td>Washington University polyomavirus</td><td>WUPyV</td><td>Nasopharyngeal tissue</td><td>Gaynor et al. (2007)</td><td>Respiratory disease</td></tr><tr><td>Merkel cell polyomavirus</td><td>MCPyV</td><td>Skin lesions, Merkel cell carcinoma patient</td><td>Feng et al. (2008)</td><td>Merkel cell carcinoma</td></tr><tr><td>Human polyomavirus 6</td><td>HPyV6</td><td>Normal skin</td><td>Schowalter et al. (2010)</td><td>Keratoacanthoma Kimura disease</td></tr><tr><td>Human polyomavirus 7</td><td>HPyV7</td><td>Normal skin</td><td>Schowalter et al. (2010)</td><td>Unknown</td></tr><tr><td>Trichodysplasia spinulosa-associated polyomavirus</td><td>TSPyV</td><td>Trichodysplasia spinulosa, skin lesions</td><td>van der Meijden et al. (2015)</td><td>Trichodysplasia spinulosa</td></tr><tr><td>Human polyomavirus 9</td><td>HPyV9</td><td>Blood, skin, urine, kidney transplant recipient</td><td>Scuda et al. (2011)</td><td>Unknown</td></tr><tr><td>Malawi polyomavirus</td><td>MWPyV</td><td>Stool, a patient with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome</td><td>Buck et al. (2012)</td><td>Unknown</td></tr><tr><td>Human polyomavirus 12</td><td>HPyV12</td><td>Resected human liver tissue</td><td>Korup et al. (2013)</td><td>Unknown</td></tr><tr><td>St. Louis polyomavirus</td><td>STPyV</td><td>Stool samples, healthy child</td><td>Lim et al. (2013), Pastrana et al. (2013)</td><td>Unknown</td></tr><tr><td>MX polyomavirus</td><td>MXPyV</td><td>Stool samples from children</td><td>Yu et al. (2012)</td><td>Unknown</td></tr><tr><td>New Jersey polyomavirus</td><td>NJPyV</td><td>Biopsy from the swollen endothelial cells, pancreatic transplant recipient</td><td>Mishra et al. (2014)</td><td>Unknown</td></tr></tbody></table>
Currently known human polyomaviruses

<table><thead><tr><th>Full names</th><th>Abbreviations</th><th>Source of isolation</th><th>Time of discovery</th><th>Associated disease</th></tr></thead><tbody><tr><td>JC virus</td><td>JCPyV</td><td>Brain, PML patient</td><td>Padgett et al. (1971)</td><td>Progressive multifocal leukoencephalopathy</td></tr><tr><td>BK virus</td><td>BKPyV</td><td>Urine, kidney transplant recipient</td><td>Gardner et al. (1971)</td><td>BK virus-associated nephropathy, Hemorrhagic cystitis</td></tr><tr><td>Karolinska Institute polyomavirus</td><td>KIPyV</td><td>Nasopharyngeal tissue</td><td>Allander et al. (2007)</td><td>Respiratory disease</td></tr><tr><td>Washington University polyomavirus</td><td>WUPyV</td><td>Nasopharyngeal tissue</td><td>Gaynor et al. (2007)</td><td>Respiratory disease</td></tr><tr><td>Merkel cell polyomavirus</td><td>MCPyV</td><td>Skin lesions, Merkel cell carcinoma patient</td><td>Feng et al. (2008)</td><td>Merkel cell carcinoma</td></tr><tr><td>Human polyomavirus 6</td><td>HPyV6</td><td>Normal skin</td><td>Schowalter et al. (2010)</td><td>Keratoacanthoma Kimura disease</td></tr><tr><td>Human polyomavirus 7</td><td>HPyV7</td><td>Normal skin</td><td>Schowalter et al. (2010)</td><td>Unknown</td></tr><tr><td>Trichodysplasia spinulosa-associated polyomavirus</td><td>TSPyV</td><td>Trichodysplasia spinulosa, skin lesions</td><td>van der Meijden et al. (2015)</td><td>Trichodysplasia spinulosa</td></tr><tr><td>Human polyomavirus 9</td><td>HPyV9</td><td>Blood, skin, urine, kidney transplant recipient</td><td>Scuda et al. (2011)</td><td>Unknown</td></tr><tr><td>Malawi polyomavirus</td><td>MWPyV</td><td>Stool, a patient with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome</td><td>Buck et al. (2012)</td><td>Unknown</td></tr><tr><td>Human polyomavirus 12</td><td>HPyV12</td><td>Resected human liver tissue</td><td>Korup et al. (2013)</td><td>Unknown</td></tr><tr><td>St. Louis polyomavirus</td><td>STPyV</td><td>Stool samples, healthy child</td><td>Lim et al. (2013), Pastrana et al. (2013)</td><td>Unknown</td></tr><tr><td>MX polyomavirus</td><td>MXPyV</td><td>Stool samples from children</td><td>Yu et al. (2012)</td><td>Unknown</td></tr><tr><td>New Jersey polyomavirus</td><td>NJPyV</td><td>Biopsy from the swollen endothelial cells, pancreatic transplant recipient</td><td>Mishra et al. (2014)</td><td>Unknown</td></tr></tbody></table>
<caption>TABLE 2</caption>

Polyomavirus genomes generate the novel viral proteins due to alternative splicing

<table><thead><tr><th>Virus names</th><th>Early/late gene expression</th><th>Putative protein</th><th>No. of amino acids</th><th>Expected size (kDa)</th><th>References</th></tr></thead><tbody><tr><td>TSPyV</td><td>Early</td><td>Top T</td><td>332</td><td>38</td><td>van der Meijden et al. (2015)</td></tr><tr><td>TSPyV</td><td>Early</td><td>Tiny T</td><td>85</td><td>10</td><td>van der Meijden et al. (2015)</td></tr><tr><td>TSPyV</td><td>Early</td><td>Small T*</td><td>197</td><td>24</td><td>van der Meijden et al. (2015)</td></tr><tr><td>TSPyV</td><td>Early</td><td>21 kT</td><td>184</td><td>21</td><td>van der Meijden et al. (2015)</td></tr><tr><td>MCPyV</td><td>Early</td><td>57 kT</td><td>432</td><td>48</td><td>Carter et al. (2013)</td></tr><tr><td>MCPyV</td><td>Early</td><td>ALTO</td><td>248</td><td>27</td><td>Carter et al. (2013)</td></tr><tr><td>MPyV</td><td>Early</td><td>Top T</td><td>421</td><td>46</td><td>Soeda et al. (1979)</td></tr><tr><td>MPyV</td><td>Early</td><td>Tiny T</td><td>75</td><td>8</td><td>Riley et al. (1997)</td></tr><tr><td>JCPyV</td><td>Early</td><td>T165</td><td>165</td><td>18</td><td>Prins and Frisque (2001)</td></tr><tr><td>JCPyV</td><td>Early</td><td>T136</td><td>136</td><td>15</td><td>Prins and Frisque (2001)</td></tr><tr><td>JCPyV</td><td>Early</td><td>T135</td><td>135</td><td>15</td><td>Prins and Frisque (2001)</td></tr><tr><td>JCPyV</td><td>Early</td><td>T152</td><td>152</td><td>17</td><td>Prins and Frisque (2001)</td></tr><tr><td>JCPyV</td><td>Early</td><td>T147</td><td>147</td><td>16</td><td>Prins and Frisque (2001)</td></tr><tr><td>JCPyV</td><td>Late</td><td>ORF1</td><td>58</td><td>6.4</td><td>Saribas, Devoto et al. 2018</td></tr><tr><td>JCPyV</td><td>Late</td><td>ORF2</td><td>72</td><td>7.9</td><td>Saribas, Devoto et al. 2018</td></tr><tr><td>JCPyV</td><td>Late</td><td>Agnoprotein</td><td>71</td><td>7.8</td><td>Del Valle et al. (2002)</td></tr><tr><td>SV40PyV</td><td>Early</td><td>17 kDa</td><td>135</td><td>17</td><td>Zerrahn et al. (1993)</td></tr><tr><td>SV40PyV</td><td>Late</td><td>Agnoprotein</td><td>62</td><td>6.8</td><td>Gilbert et al. (1981)</td></tr><tr><td>BKPyV</td><td>Early</td><td>TruncTAg</td><td>ND</td><td>17–20</td><td>Abend et al. (2009)</td></tr><tr><td>BKPyV</td><td>Late</td><td>Agnoprotein</td><td>68</td><td>7.5</td><td>Rinaldo et al. (1998)</td></tr></tbody></table>

Note. All polyomaviruses universally express large and small T antigens and they are not included in this table.

ND: not determined.
<caption>TABLE 2</caption>

Polyomavirus genomes generate the novel viral proteins due to alternative splicing

<table><thead><tr><th>Virus names</th><th>Early/late gene expression</th><th>Putative protein</th><th>No. of amino acids</th><th>Expected size (kDa)</th><th>References</th></tr></thead><tbody><tr><td>TSPyV</td><td>Early</td><td>Top T</td><td>332</td><td>38</td><td>van der Meijden et al. (2015)</td></tr><tr><td>TSPyV</td><td>Early</td><td>Tiny T</td><td>85</td><td>10</td><td>van der Meijden et al. (2015)</td></tr><tr><td>TSPyV</td><td>Early</td><td>Small T*</td><td>197</td><td>24</td><td>van der Meijden et al. (2015)</td></tr><tr><td>TSPyV</td><td>Early</td><td>21 kT</td><td>184</td><td>21</td><td>van der Meijden et al. (2015)</td></tr><tr><td>MCPyV</td><td>Early</td><td>57 kT</td><td>432</td><td>48</td><td>Carter et al. (2013)</td></tr><tr><td>MCPyV</td><td>Early</td><td>ALTO</td><td>248</td><td>27</td><td>Carter et al. (2013)</td></tr><tr><td>MPyV</td><td>Early</td><td>Top T</td><td>421</td><td>46</td><td>Soeda et al. (1979)</td></tr><tr><td>MPyV</td><td>Early</td><td>Tiny T</td><td>75</td><td>8</td><td>Riley et al. (1997)</td></tr><tr><td>JCPyV</td><td>Early</td><td>T165</td><td>165</td><td>18</td><td>Prins and Frisque (2001)</td></tr><tr><td>JCPyV</td><td>Early</td><td>T136</td><td>136</td><td>15</td><td>Prins and Frisque (2001)</td></tr><tr><td>JCPyV</td><td>Early</td><td>T135</td><td>135</td><td>15</td><td>Prins and Frisque (2001)</td></tr><tr><td>JCPyV</td><td>Early</td><td>T152</td><td>152</td><td>17</td><td>Prins and Frisque (2001)</td></tr><tr><td>JCPyV</td><td>Early</td><td>T147</td><td>147</td><td>16</td><td>Prins and Frisque (2001)</td></tr><tr><td>JCPyV</td><td>Late</td><td>ORF1</td><td>58</td><td>6.4</td><td>Saribas, Devoto et al. 2018</td></tr><tr><td>JCPyV</td><td>Late</td><td>ORF2</td><td>72</td><td>7.9</td><td>Saribas, Devoto et al. 2018</td></tr><tr><td>JCPyV</td><td>Late</td><td>Agnoprotein</td><td>71</td><td>7.8</td><td>Del Valle et al. (2002)</td></tr><tr><td>SV40PyV</td><td>Early</td><td>17 kDa</td><td>135</td><td>17</td><td>Zerrahn et al. (1993)</td></tr><tr><td>SV40PyV</td><td>Late</td><td>Agnoprotein</td><td>62</td><td>6.8</td><td>Gilbert et al. (1981)</td></tr><tr><td>BKPyV</td><td>Early</td><td>TruncTAg</td><td>ND</td><td>17–20</td><td>Abend et al. (2009)</td></tr><tr><td>BKPyV</td><td>Late</td><td>Agnoprotein</td><td>68</td><td>7.5</td><td>Rinaldo et al. (1998)</td></tr></tbody></table>

Note. All polyomaviruses universally express large and small T antigens and they are not included in this table.

ND: not determined.
<caption>TABLE 3</caption>

Predicted and/or validated functional motifs of agnoprotein

<table><thead><tr><th>Motif sequences</th><th>Amino acid position</th><th>Modification/organelle targeting</th><th>Website/reference</th></tr></thead><tbody><tr><td>MVLRQL.SRKASVKV</td><td>1-14</td><td>Mitochondria targeting signal</td><td>http://mitf.cbrc.jp/MitoFates/cgi-bin/top.cgi</td></tr><tr><td>VLRQ</td><td>2-5</td><td>Endoplasmic reticulum membrane retention signal</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>SRK</td><td>7-9</td><td>Phosphorylation by protein kinase C (PKC)</td><td>Sariyer et al. (2006)</td></tr><tr><td>RKAS</td><td>8-11</td><td>Phosphorylation by cAMP-dependent protein kinase A (cAMP-PKA)</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>SVK</td><td>11-13</td><td>Phosphorylation by PKC</td><td>Sariyer et al. (2006), Johannessen et al. (2008)</td></tr><tr><td>TKK</td><td>21-23</td><td>Phosphorylation by PKC</td><td>Sariyer et al. (2006), Johannessen et al. (2008)</td></tr><tr><td>RKASVKVSKTWSGTKKR</td><td>8-24</td><td>Bipartite nuclear localization signal</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>IFLLEFLLD</td><td>30-38</td><td>Nuclear export signal (NES)</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>TGED</td><td>41-44</td><td>Phosphorylation by Casein Kinase II (CKII)</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>DGKK</td><td>48-51</td><td>Amidation</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>EPKA</td><td>66-69</td><td>Endoplasmic reticulum membrane retention signal</td><td>https://wolfpsort.hgc.jp/</td></tr></tbody></table>
<caption>TABLE 3</caption>

Predicted and/or validated functional motifs of agnoprotein

<table><thead><tr><th>Motif sequences</th><th>Amino acid position</th><th>Modification/organelle targeting</th><th>Website/reference</th></tr></thead><tbody><tr><td>MVLRQL.SRKASVKV</td><td>1-14</td><td>Mitochondria targeting signal</td><td>http://mitf.cbrc.jp/MitoFates/cgi-bin/top.cgi</td></tr><tr><td>VLRQ</td><td>2-5</td><td>Endoplasmic reticulum membrane retention signal</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>SRK</td><td>7-9</td><td>Phosphorylation by protein kinase C (PKC)</td><td>Sariyer et al. (2006)</td></tr><tr><td>RKAS</td><td>8-11</td><td>Phosphorylation by cAMP-dependent protein kinase A (cAMP-PKA)</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>SVK</td><td>11-13</td><td>Phosphorylation by PKC</td><td>Sariyer et al. (2006), Johannessen et al. (2008)</td></tr><tr><td>TKK</td><td>21-23</td><td>Phosphorylation by PKC</td><td>Sariyer et al. (2006), Johannessen et al. (2008)</td></tr><tr><td>RKASVKVSKTWSGTKKR</td><td>8-24</td><td>Bipartite nuclear localization signal</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>IFLLEFLLD</td><td>30-38</td><td>Nuclear export signal (NES)</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>TGED</td><td>41-44</td><td>Phosphorylation by Casein Kinase II (CKII)</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>DGKK</td><td>48-51</td><td>Amidation</td><td>https://wolfpsort.hgc.jp/</td></tr><tr><td>EPKA</td><td>66-69</td><td>Endoplasmic reticulum membrane retention signal</td><td>https://wolfpsort.hgc.jp/</td></tr></tbody></table>
<caption>TABLE 4</caption>

Viral and cellular binding partners of agnoprotein and associated functions

<table><thead><tr><th>Polyomavirus names</th><th>Binding partners</th><th>Binding domain of agnoprotein</th><th>Associated functions</th><th>References</th></tr></thead><tbody><tr><td>JCVPyV</td><td>JCV LT-Ag</td><td>1-36</td><td>Inhibition of JCV transcription and replication</td><td>Safak et al. (2001)</td></tr><tr><td>JCVPyV</td><td>JCV Sm t-Ag</td><td>ND</td><td>Inhibition of PP2A-mediated dephosphorylation of agnoprotein</td><td>Sariyer et al. (2008)</td></tr><tr><td>JCVPyV</td><td>JCV VP1</td><td>ND</td><td>Involved in virion assembly</td><td>Suzuki et al. (2012)</td></tr><tr><td>JCVPyV</td><td>HIV-1 Tat</td><td>18-54</td><td>Inhibition of Tat-mediated HIV promoter activation</td><td>Kaniowska et al. (2006)</td></tr><tr><td>JCVPyV</td><td>p53</td><td>1-36</td><td>Suppression of cell cycle progression</td><td>Darbinyan et al. (2002)</td></tr><tr><td>JCVPyV</td><td>Ku70</td><td>1-36</td><td>Inhibition of double-strand break repair</td><td>Darbinyan et al. (2004)</td></tr><tr><td>JCVPyV</td><td>PP2A</td><td>18-36</td><td>Dephosphorylation of agnoprotein</td><td>Sariyer et al. (2008)</td></tr><tr><td>JCVPyV</td><td>YB-1</td><td>1-36)</td><td>Inhibition of YB-1-mediated transcription of JCV promoters</td><td>Safak et al. (2002)</td></tr><tr><td>JCVPyV</td><td>FEZ1</td><td>ND</td><td>Inhibition of FEZ1-mediated neurite outgrowth</td><td>Suzuki et al. (2005)</td></tr><tr><td>JCVPyV</td><td>HP1α</td><td>1-18</td><td>Facilitation of nuclear export of JCV virions</td><td>Okada et al. (2005)</td></tr><tr><td>JCVPyV</td><td>AP-3</td><td>ND</td><td>Inhibition of PB-3-mediated vesicular trafficking</td><td>Suzuki et al. (2013)</td></tr><tr><td>BKPyV</td><td>α-SNAP</td><td>1-15</td><td>Inhibition of vesicle transport</td><td>Johannessen et al. (2011)</td></tr><tr><td>BKPyV</td><td>PCNA</td><td>1-15</td><td>Inhibition of DNA replication</td><td>Gerits et al. (2015)</td></tr></tbody></table>
<caption>TABLE 4</caption>

Viral and cellular binding partners of agnoprotein and associated functions

<table><thead><tr><th>Polyomavirus names</th><th>Binding partners</th><th>Binding domain of agnoprotein</th><th>Associated functions</th><th>References</th></tr></thead><tbody><tr><td>JCVPyV</td><td>JCV LT-Ag</td><td>1-36</td><td>Inhibition of JCV transcription and replication</td><td>Safak et al. (2001)</td></tr><tr><td>JCVPyV</td><td>JCV Sm t-Ag</td><td>ND</td><td>Inhibition of PP2A-mediated dephosphorylation of agnoprotein</td><td>Sariyer et al. (2008)</td></tr><tr><td>JCVPyV</td><td>JCV VP1</td><td>ND</td><td>Involved in virion assembly</td><td>Suzuki et al. (2012)</td></tr><tr><td>JCVPyV</td><td>HIV-1 Tat</td><td>18-54</td><td>Inhibition of Tat-mediated HIV promoter activation</td><td>Kaniowska et al. (2006)</td></tr><tr><td>JCVPyV</td><td>p53</td><td>1-36</td><td>Suppression of cell cycle progression</td><td>Darbinyan et al. (2002)</td></tr><tr><td>JCVPyV</td><td>Ku70</td><td>1-36</td><td>Inhibition of double-strand break repair</td><td>Darbinyan et al. (2004)</td></tr><tr><td>JCVPyV</td><td>PP2A</td><td>18-36</td><td>Dephosphorylation of agnoprotein</td><td>Sariyer et al. (2008)</td></tr><tr><td>JCVPyV</td><td>YB-1</td><td>1-36)</td><td>Inhibition of YB-1-mediated transcription of JCV promoters</td><td>Safak et al. (2002)</td></tr><tr><td>JCVPyV</td><td>FEZ1</td><td>ND</td><td>Inhibition of FEZ1-mediated neurite outgrowth</td><td>Suzuki et al. (2005)</td></tr><tr><td>JCVPyV</td><td>HP1α</td><td>1-18</td><td>Facilitation of nuclear export of JCV virions</td><td>Okada et al. (2005)</td></tr><tr><td>JCVPyV</td><td>AP-3</td><td>ND</td><td>Inhibition of PB-3-mediated vesicular trafficking</td><td>Suzuki et al. (2013)</td></tr><tr><td>BKPyV</td><td>α-SNAP</td><td>1-15</td><td>Inhibition of vesicle transport</td><td>Johannessen et al. (2011)</td></tr><tr><td>BKPyV</td><td>PCNA</td><td>1-15</td><td>Inhibition of DNA replication</td><td>Gerits et al. (2015)</td></tr></tbody></table>