VPAP_HCMVA
ID VPAP_HCMVA Reviewed; 433 AA.
AC P16790; Q7M6P1;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1990, sequence version 1.
DT 03-AUG-2022, entry version 99.
DE RecName: Full=DNA polymerase processivity factor;
DE AltName: Full=Polymerase accessory protein;
DE Short=PAP;
DE AltName: Full=Protein ICP36;
GN Name=UL44;
OS Human cytomegalovirus (strain AD169) (HHV-5) (Human herpesvirus 5).
OC Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC Herpesvirales; Herpesviridae; Betaherpesvirinae; Cytomegalovirus.
OX NCBI_TaxID=10360;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-27.
RX PubMed=2538657; DOI=10.1128/jvi.63.4.1783-1791.1989;
RA Leach F.S., Mocarski E.S.;
RT "Regulation of cytomegalovirus late-gene expression: differential use of
RT three start sites in the transcriptional activation of ICP36 gene
RT expression.";
RL J. Virol. 63:1783-1791(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=2161319; DOI=10.1007/978-3-642-74980-3_6;
RA Chee M.S., Bankier A.T., Beck S., Bohni R., Brown C.M., Cerny R.,
RA Horsnell T., Hutchison C.A. III, Kouzarides T., Martignetti J.A.,
RA Preddie E., Satchwell S.C., Tomlinson P., Weston K.M., Barrell B.G.;
RT "Analysis of the protein-coding content of the sequence of human
RT cytomegalovirus strain AD169.";
RL Curr. Top. Microbiol. Immunol. 154:125-169(1990).
RN [3]
RP GENOME REANNOTATION.
RX PubMed=12533697; DOI=10.1099/vir.0.18606-0;
RA Davison A.J., Dolan A., Akter P., Addison C., Dargan D.J., Alcendor D.J.,
RA McGeoch D.J., Hayward G.S.;
RT "The human cytomegalovirus genome revisited: comparison with the chimpanzee
RT cytomegalovirus genome.";
RL J. Gen. Virol. 84:17-28(2003).
RN [4]
RP ERRATUM OF PUBMED:12533697.
RA Davison A.J., Dolan A., Akter P., Addison C., Dargan D.J., Alcendor D.J.,
RA McGeoch D.J., Hayward G.S.;
RL J. Gen. Virol. 84:1053-1053(2003).
RN [5]
RP INTERACTION WITH UL54, AND MUTAGENESIS OF ILE-135.
RX PubMed=14671097; DOI=10.1128/jvi.78.1.158-167.2004;
RA Loregian A., Appleton B.A., Hogle J.M., Coen D.M.;
RT "Residues of human cytomegalovirus DNA polymerase catalytic subunit UL54
RT that are necessary and sufficient for interaction with the accessory
RT protein UL44.";
RL J. Virol. 78:158-167(2004).
RN [6]
RP IDENTIFICATION.
RX PubMed=15452216; DOI=10.1128/jvi.78.20.10960-10966.2004;
RA Varnum S.M., Streblow D.N., Monroe M.E., Smith P., Auberry K.J.,
RA Pasa-Tolic L., Wang D., Camp D.G. II, Rodland K., Wiley S., Britt W.,
RA Shenk T., Smith R.D., Nelson J.A.;
RT "Identification of proteins in human cytomegalovirus (HCMV) particles: the
RT HCMV proteome.";
RL J. Virol. 78:10960-10966(2004).
RN [7]
RP ERRATUM OF PUBMED:15452216.
RA Varnum S.M., Streblow D.N., Monroe M.E., Smith P., Auberry K.J.,
RA Pasa-Tolic L., Wang D., Camp D.G. II, Rodland K., Wiley S., Britt W.,
RA Shenk T., Smith R.D., Nelson J.A.;
RL J. Virol. 78:13395-13395(2004).
RN [8]
RP OLIGOMERIZATION.
RX PubMed=18842734; DOI=10.1128/jvi.01193-08;
RA Sinigalia E., Alvisi G., Mercorelli B., Coen D.M., Pari G.S., Jans D.A.,
RA Ripalti A., Palu G., Loregian A.;
RT "Role of homodimerization of human cytomegalovirus DNA polymerase accessory
RT protein UL44 in origin-dependent DNA replication in cells.";
RL J. Virol. 82:12574-12579(2008).
RN [9]
RP INTERACTION WITH UL114.
RX PubMed=18599070; DOI=10.1016/j.jmb.2008.05.028;
RA Ranneberg-Nilsen T., Dale H.A., Luna L., Slettebakk R., Sundheim O.,
RA Rollag H., Bjoras M.;
RT "Characterization of human cytomegalovirus uracil DNA glycosylase (UL114)
RT and its interaction with polymerase processivity factor (UL44).";
RL J. Mol. Biol. 381:276-288(2008).
RN [10]
RP INTERACTION WITH UL84.
RX PubMed=19457994; DOI=10.1128/jvi.00663-09;
RA Strang B.L., Sinigalia E., Silva L.A., Coen D.M., Loregian A.;
RT "Analysis of the association of the human cytomegalovirus DNA polymerase
RT subunit UL44 with the viral DNA replication factor UL84.";
RL J. Virol. 83:7581-7589(2009).
RN [11]
RP INTERACTION WITH UL112/113, AND FUNCTION.
RX PubMed=20538862; DOI=10.1128/jvi.00189-10;
RA Kim Y.E., Ahn J.H.;
RT "Role of the specific interaction of UL112-113 p84 with UL44 DNA polymerase
RT processivity factor in promoting DNA replication of human
RT cytomegalovirus.";
RL J. Virol. 84:8409-8421(2010).
RN [12]
RP SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=20739543; DOI=10.1128/jvi.01033-10;
RA Silva L.A., Loregian A., Pari G.S., Strang B.L., Coen D.M.;
RT "The carboxy-terminal segment of the human cytomegalovirus DNA polymerase
RT accessory subunit UL44 is crucial for viral replication.";
RL J. Virol. 84:11563-11568(2010).
RN [13]
RP PHOSPHORYLATION AT SER-413; SER-415 AND SER-418, AND SUBCELLULAR LOCATION.
RX PubMed=21784501; DOI=10.1016/j.virol.2011.06.008;
RA Silva L.A., Strang B.L., Lin E.W., Kamil J.P., Coen D.M.;
RT "Sites and roles of phosphorylation of the human cytomegalovirus DNA
RT polymerase subunit UL44.";
RL Virology 417:268-280(2011).
RN [14]
RP INTERACTION WITH HOST NCL, AND FUNCTION.
RX PubMed=22318319; DOI=10.1128/mbio.00301-11;
RA Strang B.L., Boulant S., Kirchhausen T., Coen D.M.;
RT "Host cell nucleolin is required to maintain the architecture of human
RT cytomegalovirus replication compartments.";
RL MBio 3:255-260(2012).
RN [15]
RP INTERACTION WITH HOST SMARCB1.
RX PubMed=22479537; DOI=10.1371/journal.pone.0034119;
RA Ranneberg-Nilsen T., Rollag H., Slettebakk R., Backe P.H., Olsen O.,
RA Luna L., Bjoras M.;
RT "The chromatin remodeling factor SMARCB1 forms a complex with human
RT cytomegalovirus proteins UL114 and UL44.";
RL PLoS ONE 7:E34119-E34119(2012).
RN [16]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH HOST IRF3 AND HOST
RP RELA.
RX PubMed=30867312; DOI=10.1128/jvi.00181-19;
RA Fu Y.Z., Su S., Zou H.M., Guo Y., Wang S.Y., Li S., Luo M.H., Wang Y.Y.;
RT "Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral
RT Immune Responses by Suppressing IRF3- and NF-kappaB-Mediated
RT Transcription.";
RL J. Virol. 93:0-0(2019).
RN [17]
RP FUNCTION, SUMOYLATION, MUTAGENESIS OF LYS-410, AND INTERACTION WITH HOST
RP UBC9.
RX PubMed=33967989; DOI=10.3389/fmicb.2021.652719;
RA Chen J., Li G., He H., Li X., Niu W., Cao D., Shen A.;
RT "Sumoylation of the Carboxy-Terminal of Human Cytomegalovirus DNA
RT Polymerase Processivity Factor UL44 Attenuates Viral DNA Replication.";
RL Front. Microbiol. 12:652719-652719(2021).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 1-290.
RX PubMed=15260974; DOI=10.1016/j.molcel.2004.06.018;
RA Appleton B.A., Loregian A., Filman D.J., Coen D.M., Hogle J.M.;
RT "The cytomegalovirus DNA polymerase subunit UL44 forms a C clamp-shaped
RT dimer.";
RL Mol. Cell 15:233-244(2004).
CC -!- FUNCTION: Accessory subunit of the DNA polymerase that plays an
CC essential role in viral DNA replication and acts by increasing the
CC processivity of polymerization (PubMed:20538862, PubMed:20739543,
CC PubMed:33967989). Forms dimers that binds to double-stranded DNA and
CC UL54 specifically to stimulates long chain DNA synthesis efficiently.
CC Plays an important role in maintaining the structure of viral
CC replication compartments by interacting with host nucleolin/NUC
CC (PubMed:22318319). In addition, suppresses innate immune responses
CC through effects on host IRF3 and NF-kappa-B. Mechanistically, interfere
CC with the binding of IRF3 and the p65 NF-kappa-B subunit to the
CC promoters of antiviral genes, thereby inhibiting the expression of
CC these genes (PubMed:30867312). {ECO:0000269|PubMed:20538862,
CC ECO:0000269|PubMed:20739543, ECO:0000269|PubMed:22318319,
CC ECO:0000269|PubMed:30867312, ECO:0000269|PubMed:33967989}.
CC -!- SUBUNIT: Forms homodimers. Interacts with host SMARCB1. Interacts with
CC host NCL/nucleolin; this interaction is important for the organization
CC of proteins within viral replication compartments. Interacts with
CC UL112/UL113; this interaction is necessary for efficient viral DNA
CC replication. Interacts with UL84. Interacts with the uracil DNA
CC glycosylase UL114. Interacts with the DNA polymerase catalytic subunit
CC UL54. Interacts with host IRF3 (PubMed:30867312). Interacts with host
CC RELA (PubMed:30867312). {ECO:0000269|PubMed:14671097,
CC ECO:0000269|PubMed:18599070, ECO:0000269|PubMed:19457994,
CC ECO:0000269|PubMed:20538862, ECO:0000269|PubMed:22318319,
CC ECO:0000269|PubMed:22479537}.
CC -!- SUBCELLULAR LOCATION: Virion. Host nucleus
CC {ECO:0000269|PubMed:20739543, ECO:0000269|PubMed:21784501,
CC ECO:0000269|PubMed:30867312}.
CC -!- DOMAIN: The C-terminal region is required for viral DNA synthesis.
CC {ECO:0000269|PubMed:20739543}.
CC -!- PTM: Phosphorylated by UL97 on serine residues, phosphorylation seems
CC important for UL44 nuclear entry but does not directly affect its role
CC in replication. {ECO:0000269|PubMed:21784501}.
CC -!- PTM: Sumoylated. Sumoylation on Lys-410 increases viral DNA
CC replication. {ECO:0000269|PubMed:33967989}.
CC -!- SIMILARITY: Belongs to the herpesviridae polymerase accessory protein
CC family. {ECO:0000305}.
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DR EMBL; X17403; CAA35403.1; -; Genomic_DNA.
DR EMBL; BK000394; DAA00147.1; -; Genomic_DNA.
DR PIR; S09807; QQBEV2.
DR PDB; 1T6L; X-ray; 1.85 A; A=1-290.
DR PDB; 1YYP; X-ray; 2.50 A; A=1-290.
DR PDB; 5IWD; X-ray; 2.56 A; A=1-290.
DR PDB; 5IXA; X-ray; 2.68 A; A/B=1-290.
DR PDBsum; 1T6L; -.
DR PDBsum; 1YYP; -.
DR PDBsum; 5IWD; -.
DR PDBsum; 5IXA; -.
DR SMR; P16790; -.
DR DIP; DIP-46029N; -.
DR ELM; P16790; -.
DR IntAct; P16790; 1.
DR PRIDE; P16790; -.
DR EvolutionaryTrace; P16790; -.
DR Proteomes; UP000008991; Genome.
DR Proteomes; UP000008992; Genome.
DR GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0030337; F:DNA polymerase processivity factor activity; IEA:InterPro.
DR GO; GO:0039686; P:bidirectional double-stranded viral DNA replication; IDA:UniProtKB.
DR GO; GO:0006260; P:DNA replication; IEA:UniProtKB-KW.
DR GO; GO:0039644; P:suppression by virus of host NF-kappaB cascade; IEA:UniProtKB-KW.
DR GO; GO:0039548; P:suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity; IEA:UniProtKB-KW.
DR InterPro; IPR004997; Herpes_PAP.
DR Pfam; PF03325; Herpes_PAP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; DNA replication; DNA-binding; Host nucleus;
KW Host-virus interaction; Inhibition of host innate immune response by virus;
KW Inhibition of host IRF3 by virus; Inhibition of host NF-kappa-B by virus;
KW Inhibition of host RLR pathway by virus; Isopeptide bond; Phosphoprotein;
KW Reference proteome; Ubl conjugation; Viral DNA replication;
KW Viral immunoevasion; Virion.
FT CHAIN 1..433
FT /note="DNA polymerase processivity factor"
FT /id="PRO_0000116070"
FT REGION 274..433
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 363..377
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 413
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:21784501"
FT MOD_RES 415
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:21784501"
FT MOD_RES 418
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:21784501"
FT CROSSLNK 410
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in host SUMO1)"
FT /evidence="ECO:0000269|PubMed:33967989"
FT MUTAGEN 135
FT /note="I->A: Complete loss of interaction with UL54."
FT /evidence="ECO:0000269|PubMed:14671097"
FT MUTAGEN 410
FT /note="K->A: Complete loss of sumoylation and enhanced
FT viral DNA synthesis."
FT /evidence="ECO:0000269|PubMed:33967989"
FT STRAND 12..15
FT /evidence="ECO:0007829|PDB:1T6L"
FT HELIX 17..26
FT /evidence="ECO:0007829|PDB:1T6L"
FT HELIX 28..32
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 39..43
FT /evidence="ECO:0007829|PDB:1T6L"
FT TURN 44..46
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 47..54
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 57..63
FT /evidence="ECO:0007829|PDB:1T6L"
FT HELIX 65..67
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 68..71
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 78..84
FT /evidence="ECO:0007829|PDB:1T6L"
FT TURN 85..87
FT /evidence="ECO:0007829|PDB:1T6L"
FT HELIX 90..93
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 101..105
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 109..118
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 121..129
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 134..136
FT /evidence="ECO:0007829|PDB:1YYP"
FT STRAND 144..148
FT /evidence="ECO:0007829|PDB:1T6L"
FT HELIX 150..160
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 178..185
FT /evidence="ECO:0007829|PDB:1T6L"
FT TURN 186..189
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 190..195
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 200..203
FT /evidence="ECO:0007829|PDB:1T6L"
FT TURN 206..208
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 209..213
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 216..222
FT /evidence="ECO:0007829|PDB:1T6L"
FT HELIX 223..233
FT /evidence="ECO:0007829|PDB:1T6L"
FT HELIX 234..236
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 240..257
FT /evidence="ECO:0007829|PDB:1T6L"
FT STRAND 259..268
FT /evidence="ECO:0007829|PDB:1T6L"
SQ SEQUENCE 433 AA; 46233 MW; E3BDF4C05E4C040A CRC64;
MDRKTRLSEP PTLALRLKPY KTAIQQLRSV IRALKENTTV TFLPTPSLIL QTVRSHCVSK
ITFNSSCLYI TDKSFQPKTI NNSTPLLGNF MYLTSSKDLT KFYVQDISDL SAKISMCAPD
FNMEFSSACV HGQDIVRESE NSAVHVDLDF GVVADLLKWI GPHTRVKRNV KKAPCPTGTV
QILVHAGPPA IKFILTNGSE LEFTANNRVS FHGVKNMRIN VQLKNFYQTL LNCAVTKLPC
TLRIVTEHDT LLYVASRNGL FAVENFLTEE PFQRGDPFDK NYVGNSGKSR GGGGGGGSLS
SLANAGGLHD DGPGLDNDLM NEPMGLGGLG GGGGGGGKKH DRGGGGGSGT RKMSSGGGGG
DHDHGLSSKE KYEQHKITSY LTSKGGSGGG GGGGGGGLDR NSGNYFNDAK EESDSEDSVT
FEFVPNTKKQ KCG
