CFLA_MCV1
ID CFLA_MCV1 Reviewed; 241 AA.
AC Q98325; O11298;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1997, sequence version 1.
DT 03-AUG-2022, entry version 113.
DE RecName: Full=Viral CASP8 and FADD-like apoptosis regulator;
DE Short=v-CFLAR;
DE AltName: Full=Viral FLICE-inhibitory protein;
DE Short=v-FLIP;
GN OrderedLocusNames=MC159L; ORFNames=H-H2.2;
OS Molluscum contagiosum virus subtype 1 (MOCV) (MCVI).
OC Viruses; Varidnaviria; Bamfordvirae; Nucleocytoviricota; Pokkesviricetes;
OC Chitovirales; Poxviridae; Chordopoxvirinae; Molluscipoxvirus.
OX NCBI_TaxID=10280;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=8670425; DOI=10.1126/science.273.5276.813;
RA Senkevich T.G., Bugert J.J., Sisler J.R., Koonin E.V., Darai G., Moss B.;
RT "Genome sequence of a human tumorigenic poxvirus: prediction of specific
RT host response-evasion genes.";
RL Science 273:813-816(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 91-241.
RX PubMed=9208457; DOI=10.1023/a:1007991508159;
RA Moratilla M., Agromayor M., Nunez A., Funes J.M., Varas A.J.,
RA Lopez-Estebaranz J.L., Esteban M., Martin-Gallardo A.;
RT "A random DNA sequencing, computer-based approach for the generation of a
RT gene map of Molluscum contagiosum virus.";
RL Virus Genes 14:73-80(1997).
RN [3]
RP FUNCTION.
RX PubMed=9087414; DOI=10.1038/386517a0;
RA Thome M., Schneider P., Hofmann K., Fickenscher H., Meinl E., Neipel F.,
RA Mattmann C., Burns K., Bodmer J.-L., Schroeter M., Scaffidi C.,
RA Krammer P.H., Peter M.E., Tschopp J.;
RT "Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death
RT receptors.";
RL Nature 386:517-521(1997).
RN [4]
RP FUNCTION.
RX PubMed=9037025; DOI=10.1073/pnas.94.4.1172;
RA Bertin J., Armstrong R.C., Ottilie S., Martin D.A., Wang Y., Banks S.,
RA Wang G.-H., Senkevich T.G., Alnemri E.S., Moss B., Lenardo M.J.,
RA Tomaselli K.J., Cohen J.I.;
RT "Death effector domain-containing herpesvirus and poxvirus proteins inhibit
RT both Fas- and TNFR1-induced apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:1172-1176(1997).
RN [5]
RP CHARACTERIZATION.
RX PubMed=10526240; DOI=10.1046/j.1365-2443.1999.00280.x;
RA Tsukumo S., Yonehara S.;
RT "Requirement of cooperative functions of two repeated death effector
RT domains in caspase-8 and in MC159 for induction and inhibition of
RT apoptosis, respectively.";
RL Genes Cells 4:541-549(1999).
RN [6]
RP FUNCTION, AND INTERACTION WITH HOST TRAF2.
RX PubMed=16040075; DOI=10.1016/j.virol.2005.06.036;
RA Murao L.E., Shisler J.L.;
RT "The MCV MC159 protein inhibits late, but not early, events of TNF-alpha-
RT induced NF-kappaB activation.";
RL Virology 340:255-264(2005).
RN [7]
RP FUNCTION, AND INTERACTION WITH HOST IKBKG.
RX PubMed=22301546; DOI=10.4049/jimmunol.1100136;
RA Randall C.M., Jokela J.A., Shisler J.L.;
RT "The MC159 protein from the molluscum contagiosum poxvirus inhibits NF-
RT kappaB activation by interacting with the IkappaB kinase complex.";
RL J. Immunol. 188:2371-2379(2012).
RN [8]
RP FUNCTION, AND INTERACTION WITH HOST IKBKG.
RX PubMed=28515292; DOI=10.1128/jvi.00276-17;
RA Biswas S., Shisler J.L.;
RT "Molluscum contagiosum virus MC159 abrogates cIAP1-NEMO interactions and
RT inhibits NEMO polyubiquitination.";
RL J. Virol. 91:0-0(2017).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.20 ANGSTROMS), AND INTERACTION WITH HOST FAS AND
RP FADD.
RX PubMed=16364918; DOI=10.1016/j.molcel.2005.10.023;
RA Yang J.K., Wang L., Zheng L., Wan F., Ahmed M., Lenardo M.J., Wu H.;
RT "Crystal structure of MC159 reveals molecular mechanism of DISC assembly
RT and FLIP inhibition.";
RL Mol. Cell 20:939-949(2005).
RN [10]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH HOST SH3BP4, AND
RP MUTAGENESIS OF PRO-8 AND PRO-11.
RX PubMed=30842330; DOI=10.1128/jvi.01613-18;
RA Schmotz C., Ugurlu H., Vilen S., Shrestha S., Fagerlund R., Saksela K.;
RT "MC159 of molluscum contagiosum virus suppresses autophagy by recruiting
RT cellular SH3BP4 via an SH3 domain-mediated interaction.";
RL J. Virol. 0:0-0(2019).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) OF 1-183, AND DOMAIN.
RX PubMed=16317000; DOI=10.1074/jbc.m511074200;
RA Li F.Y., Jeffrey P.D., Yu J.W., Shi Y.;
RT "Crystal structure of a viral FLIP: insights into FLIP-mediated inhibition
RT of death receptor signaling.";
RL J. Biol. Chem. 281:2960-2968(2006).
CC -!- FUNCTION: Inhibits TNFRSF1A, TNFRSF6/FAS and TNFRSF12 induced
CC apoptosis. Directs the degradation of host NFKBIB but not NFKBIA.
CC Suppresses also host NF-kappa-B activation by interacting with and
CC preventing ubiquitination of host NEMO/IKBKG, the NF-kappa-B essential
CC modulator subunit of the IKK complex (PubMed:28515292). Interferes with
CC host CASP8/caspase-8 recruitment and activation at the death-inducing
CC signaling complex (DISC). May lead to higher virus production and
CC contribute to virus persistence and oncogenicity. Participates also in
CC the inhibition of host autophagy by interacting with host SH3BP4
CC (PubMed:30842330). {ECO:0000269|PubMed:16040075,
CC ECO:0000269|PubMed:22301546, ECO:0000269|PubMed:28515292,
CC ECO:0000269|PubMed:30842330, ECO:0000269|PubMed:9037025,
CC ECO:0000269|PubMed:9087414}.
CC -!- SUBUNIT: Associates with the death-inducing signaling complex (DISC)
CC formed by TNFRSF6/FAS, FADD and CASP8. Interacts with FADD
CC (PubMed:16364918). Interacts with host TRAF2 (PubMed:16040075).
CC Interacts with host NEMO/IKBKG (via N-terminus)(PubMed:28515292).
CC Interacts with host SH3BP4; this interaction plays an important in the
CC suppression of host autophagy (PubMed:30842330).
CC {ECO:0000269|PubMed:16040075, ECO:0000269|PubMed:16364918,
CC ECO:0000269|PubMed:22301546, ECO:0000269|PubMed:28515292,
CC ECO:0000269|PubMed:30842330}.
CC -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000269|PubMed:30842330}.
CC Host nucleus {ECO:0000269|PubMed:30842330}.
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DR EMBL; U60315; AAC55287.1; -; Genomic_DNA.
DR EMBL; U86888; AAB57923.1; -; Genomic_DNA.
DR PIR; T30761; T30761.
DR RefSeq; NP_044110.1; NC_001731.1.
DR PDB; 2BBR; X-ray; 1.20 A; A=1-187.
DR PDB; 2BBZ; X-ray; 3.80 A; A/B/C/D=1-241.
DR PDB; 2F1S; X-ray; 1.40 A; A=1-183.
DR PDBsum; 2BBR; -.
DR PDBsum; 2BBZ; -.
DR PDBsum; 2F1S; -.
DR SMR; Q98325; -.
DR GeneID; 1487017; -.
DR KEGG; vg:1487017; -.
DR Reactome; R-HSA-140534; Caspase activation via Death Receptors in the presence of ligand.
DR EvolutionaryTrace; Q98325; -.
DR Proteomes; UP000000869; Genome.
DR GO; GO:0030430; C:host cell cytoplasm; IDA:UniProtKB.
DR GO; GO:0042025; C:host cell nucleus; IDA:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IEA:InterPro.
DR GO; GO:0060545; P:positive regulation of necroptotic process; IMP:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:InterPro.
DR GO; GO:0019050; P:suppression by virus of host apoptotic process; IDA:UniProtKB.
DR GO; GO:0039521; P:suppression by virus of host autophagy; IDA:UniProtKB.
DR GO; GO:0039644; P:suppression by virus of host NF-kappaB cascade; IDA:UniProtKB.
DR Gene3D; 1.10.533.10; -; 2.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR001875; DED_dom.
DR InterPro; IPR002398; Pept_C14.
DR PANTHER; PTHR10454; PTHR10454; 1.
DR Pfam; PF01335; DED; 1.
DR SMART; SM00031; DED; 2.
DR SUPFAM; SSF47986; SSF47986; 2.
DR PROSITE; PS50168; DED; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Apoptosis; Host cytoplasm; Host nucleus;
KW Host-virus interaction;
KW Inhibition of host apoptosis by viral FLIP-like protein;
KW Inhibition of host autophagy by virus;
KW Modulation of host cell apoptosis by virus; Reference proteome; Repeat.
FT CHAIN 1..241
FT /note="Viral CASP8 and FADD-like apoptosis regulator"
FT /id="PRO_0000072819"
FT DOMAIN 8..78
FT /note="DED 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00065,
FT ECO:0000269|PubMed:16317000"
FT DOMAIN 95..175
FT /note="DED 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00065,
FT ECO:0000269|PubMed:16317000"
FT REGION 212..241
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MUTAGEN 8
FT /note="P->A: Complete loss of autophagy inhibition; in
FT association with A-11."
FT /evidence="ECO:0000269|PubMed:30842330"
FT MUTAGEN 11
FT /note="P->A: Complete loss of autophagy inhibition; in
FT association with A-8."
FT /evidence="ECO:0000269|PubMed:30842330"
FT HELIX 4..6
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 10..17
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 22..31
FT /evidence="ECO:0007829|PDB:2BBR"
FT TURN 32..35
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 42..51
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 57..66
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 70..77
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 81..85
FT /evidence="ECO:0007829|PDB:2BBR"
FT TURN 86..89
FT /evidence="ECO:0007829|PDB:2BBR"
FT STRAND 90..92
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 95..104
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 109..122
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 124..129
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 136..145
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 155..163
FT /evidence="ECO:0007829|PDB:2BBR"
FT HELIX 167..187
FT /evidence="ECO:0007829|PDB:2BBR"
SQ SEQUENCE 241 AA; 26940 MW; 155C9FB0B969E216 CRC64;
MSDSKEVPSL PFLRHLLEEL DSHEDSLLLF LCHDAAPGCT TVTQALCSLS QQRKLTLAAL
VEMLYVLQRM DLLKSRFGLS KEGAEQLLGT SFLTRYRKLM VCVGEELDSS ELRALRLFAC
NLNPSLSTAL SESSRFVELV LALENVGLVS PSSVSVLADM LRTLRRLDLC QQLVEYEQQE
QARYRYCYAA SPSLPVRTLR RGHGASEHEQ LCMPVQESSD SPELLRTPVQ ESSSDSPEQT
T
