ID   LTP_HHV8P               Reviewed;        2635 AA.
AC   Q2HR64;
DT   05-APR-2011, integrated into UniProtKB/Swiss-Prot.
DT   15-MAY-2007, sequence version 1.
DT   03-AUG-2022, entry version 60.
DE   RecName: Full=Large tegument protein deneddylase {ECO:0000255|HAMAP-Rule:MF_04044};
DE            EC=3.4.19.12 {ECO:0000255|HAMAP-Rule:MF_04044};
DE            EC=3.4.22.- {ECO:0000255|HAMAP-Rule:MF_04044};
GN   ORFNames=ORF64;
OS   Human herpesvirus 8 type P (isolate GK18) (HHV-8) (Kaposi's
OS   sarcoma-associated herpesvirus).
OC   Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC   Herpesvirales; Herpesviridae; Gammaherpesvirinae; Rhadinovirus.
OX   NCBI_TaxID=868565;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16760382; DOI=10.1099/vir.0.81919-0;
RA   Rezaee S.A.R., Cunningham C., Davison A.J., Blackbourn D.J.;
RT   "Kaposi's sarcoma-associated herpesvirus immune modulation: an overview.";
RL   J. Gen. Virol. 87:1781-1804(2006).
RN   [2]
RP   FUNCTION.
RX   PubMed=19640989; DOI=10.1128/jvi.00589-09;
RA   Gonzalez C.M., Wang L., Damania B.;
RT   "Kaposi's sarcoma-associated herpesvirus encodes a viral deubiquitinase.";
RL   J. Virol. 83:10224-10233(2009).
CC   -!- FUNCTION: Large tegument protein that plays multiple roles in the viral
CC       cycle. During viral entry, remains associated with the capsid while
CC       most of the tegument is detached and participates in the capsid
CC       transport toward the host nucleus. Plays a role in the routing of the
CC       capsid at the nuclear pore complex and subsequent uncoating. Within the
CC       host nucleus, acts as a deneddylase and promotes the degradation of
CC       nuclear CRLs (cullin-RING ubiquitin ligases) and thereby stabilizes
CC       nuclear CRL substrates, while cytoplasmic CRLs remain unaffected. These
CC       modifications prevent host cell cycle S-phase progression and create a
CC       favorable environment allowing efficient viral genome replication.
CC       Participates later in the secondary envelopment of capsids. Indeed,
CC       plays a linker role for the association of the outer viral tegument to
CC       the capsids together with the inner tegument protein.
CC       {ECO:0000255|HAMAP-Rule:MF_04044, ECO:0000269|PubMed:19640989}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC         and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC         residue protein attached to proteins as an intracellular targeting
CC         signal).; EC=3.4.19.12; Evidence={ECO:0000255|HAMAP-Rule:MF_04044};
CC   -!- SUBUNIT: Interacts with host CUL1 and CUL4A; these interactions inhibit
CC       the E3 ligase activity of cullins. Interacts with inner tegument
CC       protein. Interacts with capsid vertex specific component CVC2.
CC       Interacts with the major capsid protein/MCP. {ECO:0000255|HAMAP-
CC       Rule:MF_04044}.
CC   -!- SUBCELLULAR LOCATION: Virion tegument {ECO:0000255|HAMAP-
CC       Rule:MF_04044}. Host cytoplasm {ECO:0000255|HAMAP-Rule:MF_04044}. Host
CC       nucleus {ECO:0000255|HAMAP-Rule:MF_04044}. Note=Tightly associated with
CC       the capsid. {ECO:0000255|HAMAP-Rule:MF_04044}.
CC   -!- SIMILARITY: Belongs to the herpesviridae large tegument protein family.
CC       {ECO:0000255|HAMAP-Rule:MF_04044}.
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DR   EMBL; AF148805; ABD28919.1; -; Genomic_DNA.
DR   RefSeq; YP_001129421.1; NC_009333.1.
DR   PDB; 6PPB; EM; 4.30 A; n/o=1-2635.
DR   PDB; 6PPH; EM; 3.80 A; n/o=1-2635.
DR   PDBsum; 6PPB; -.
DR   PDBsum; 6PPH; -.
DR   SMR; Q2HR64; -.
DR   BioGRID; 1776944; 3.
DR   IntAct; Q2HR64; 3.
DR   PRIDE; Q2HR64; -.
DR   GeneID; 4961441; -.
DR   KEGG; vg:4961441; -.
DR   Proteomes; UP000000942; Genome.
DR   GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0019030; C:icosahedral viral capsid; IDA:CACAO.
DR   GO; GO:0019031; C:viral envelope; IDA:CACAO.
DR   GO; GO:0019033; C:viral tegument; IEA:UniProtKB-SubCell.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; IEA:UniProtKB-UniRule.
DR   GO; GO:0039648; P:modulation by virus of host protein ubiquitination; IEA:UniProtKB-UniRule.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   HAMAP; MF_04044; HSV_LTP; 1.
DR   InterPro; IPR006928; Herpes_teg_USP.
DR   InterPro; IPR034702; HSV_LTP.
DR   InterPro; IPR038765; Papain-like_cys_pep_sf.
DR   Pfam; PF04843; Herpes_teg_N; 1.
DR   SUPFAM; SSF54001; SSF54001; 1.
DR   PROSITE; PS51521; HTUSP; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Host cytoplasm; Host nucleus; Host-virus interaction;
KW   Hydrolase; Modulation of host ubiquitin pathway by viral deubiquitinase;
KW   Modulation of host ubiquitin pathway by virus; Protease;
KW   Reference proteome; Repeat; Thiol protease; Ubl conjugation pathway;
KW   Virion; Virion tegument.
FT   CHAIN           1..2635
FT                   /note="Large tegument protein deneddylase"
FT                   /id="PRO_0000406914"
FT   DOMAIN          9..223
FT                   /note="Peptidase C76"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   REGION          1..233
FT                   /note="Deubiquitination activity"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   REGION          243..497
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          316..325
FT                   /note="Interaction with inner tegument protein"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   REGION          2238..2269
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          2357..2438
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          2500..2533
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        243..259
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        260..274
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        326..341
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        371..393
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        428..442
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        483..497
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        2407..2421
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        29
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   ACT_SITE        159
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   ACT_SITE        161
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   SITE            16
FT                   /note="Important for catalytic activity"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
SQ   SEQUENCE   2635 AA;  289691 MW;  00070132EA8139AF CRC64;
     MAAQPLYMEG MASTHQANCI FGEHAGSQCL SNCVMYLASS YYNSETPLVD RASLDDVLEQ
     GMRLDLLLRK SGMLGFRQYA QLHHIPGFLR TDDWATKIFQ SPEFYGLIGQ DAAIREPFIE
     SLRSVLSRNY AGTVQYLIII CQSKAGAIVV KDKTYYMFDP HCIPNIPNSP AHVIKTNDVG
     VLLPYIATHD TEYTGCFLYF IPHDYISPEH YIANHYRTIV FEELHGPRMD ISRGVESCSI
     TEITSPSVSP APSEAPLRRD STQSQDETRP RRPRVVIPPY DPTDRPRPPH QDRPPEQAAG
     YGGNKGRGGN KGRGGKTGRG GNEGRGGHQP PDEHQPPHIT AEHMDQSDGQ GADGDMDSTP
     ANGETSVTET PGPEPNPPAR PDREPPPTPP ATPGATALLS DLTATRGQKR KFSSLKESYP
     IDSPPSDDDD VSQPSQQTAP DTEDIWIDDP LTPLYPLTDT PSFDITADVT PDNTHPEKAA
     DGDFTNKTTS TDADRYASAS QESLGTLVSP YDFTNLDTLL AELGRLGTAQ PIPVIVDRLT
     SRPFREASAL QAMDRILTHV VLEYGLVSGY STAAPSKCTH VLQFFILWGE KLGIPTEDAK
     TLLESALEIP AMCEIVQQGR LKEPTFSRHI ISKLNPCLES LHATSRQDFK SLIQAFNAEG
     IRIASRERET SMAELIETIT ARLKPNFNIV CARQDAQTIQ DGVGLLRAEV NKRNAQIAQE
     AAYFENIITA LSTFQPPPQS QQTFEVLPDL KLRTLVEHLT LVEAQVTTQT VESLQAYLQS
     AATAEHHLTN VPNVHSILSN ISNTLKVIDY VIPKFIINTD TLAPYKQQFS YLGGELASMF
     SLDWPHAPAE AVEPLPVLTS LRGKIAEALT RQENKNAVDQ ILTDAEGLLK NITDPNGAHF
     HAQAVSIPVL ENYVHNAGVL LKGEKSERFS RLKTAIQNLV SSESFITVTL HSTNLGNLVT
     NVPKLGEAFT GGPHLLTSPS VRQSLSTLCT TLLRDALDAL EKKDPALLGE GTTLALETLL
     GYGSVQDYKE TVQIISSLVG IQKLVRDQGA DKWATAVTRL TDLKSTLATT AIETATKRKL
     YRLIQRDLKE AQKHETNRAM EEWKQKVLAL DNASPERVAT LLQQAPTAKA REFAEKHFKI
     LLPVPADAPV QASPTPMEYS ASPLPDPKDI DRATSIHGEQ AWKKIQQAFK DFNFAVLRPA
     DWDALAAEYQ RRGSPLPAAV GPALSGFLET ILGTLNDIYM DKLRSFLPDA QPFQAPPFDW
     LTPYQDQVSF FLRTIGLPLV RALADKISVQ ALRLSHALQS GDLQQATVGT PLELPATEYA
     RIASNMKSVF NDHGLQVRSE VADYVEAQRA DAHTPHVPRP KIQAPKTLIP HPDAIVADGL
     PAFLKTSLLQ QEAKLLALQR ADFESLESDM RAAEAQRKAS REETQRKMAH AITQLLQQAP
     SAISGRPLSL QDPVGFLEGI IYDKVLERES YETGLEGLSW LEQTIKSITV YAPVEEKQRM
     HVLLDEVKKQ RANTETALEL EAAATHGDDA RLLQRAVDEL SPLRVKGGKA AVESWRQKIQ
     TLKSLVQEAE QAGLLLATID TVAGQAQETI SPSTLQGLYQ QGQEAMAAIK RFRDSPQLAG
     LQEKLAELQQ YVKYKKQYLE HFEATQSVVF TAFPLTQEVT IPALHYAGPF DNLERLSRYL
     HIGQTQPAPG QWLLTLPTFD PTRPACVPAG GHEPPLHRQV VFSSFLEAQI RLALSVAGPV
     PGRGLPGTPQ IRRGVEAAAC FLHQWDEISR LLPEVLDTFF HNAPLPAESS SNAFLAMCVL
     THLVYLAGRA VLGPREPEHA APDAYPREVA LAPRDLTYLL LAMWPSWISA ILKQPSHAEA
     AHACLVTLPT MLKAVPYLTL EASAGPLPAD MRHFATPEAR LFFPARWHHV NVQEKLWLRN
     DFMSLCHRSP GRARIAVLVW AVTCLDPEVI RQLWSTLRPL TADESDTASG LLRVLVEMEF
     GPPPKTPRRE AVAPGATLPP YPYGLATGER LVGQAQERSG GAGKMPVSGF EIVLGALLFR
     APLRIFSTAS THRISDFEGG FQILTPLLDC CPDREPFASL AAAPRRTVPL GDPCANIHTP
     EEIQIFARQA AWLQYTFANY QIPSTDNPIP IVVLNANNNL ENSYIPRDRK ADPLRPFYVV
     PLKPQGRWPE IMTTATTPCR LPTSPEEAGS QFARLLQSQV SATWSDIFSR VPERLAPNAP
     QKSSQTMSEI HEVAATPPLT ITPNKPTGTP HVSPEADPIT ERKRGQQPKI VADNMPSRIL
     PSLPTPKPRE PRITLPHALP VISPPAHRPS PIPHLPAPQV TEPKGVLQSK RGTLVLRPAA
     VIDPRKPVSA PITRYERTAL QPPRTEGEGR RPPDTQPVTL TFRLPPTAPT PATAALETKT
     TPPSTPPHAI DISPPQTPPM STSPHARDTS PPAEKRAAPV IRVMAPTQPS GEARVKRVEI
     EQGLSTRNEA PPLERSNHAV PAVTPRRTVA REIRIPPEIK AGWDTAPDIP LPHSSPESSP
     PTSPQPIRVD DKSPLPNLVE RYARGFLDTP SVEVMSLENQ DIAVDPGLLT RRIPSVVPMP
     HPIMWSPIVP ISLQNTDIDT AKITLISFIR RIKQKVAALS ASLAETVDRI KKWYL