ID   VGP_TAFVC               Reviewed;         676 AA.
AC   Q66810;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   27-MAR-2024, entry version 113.
DE   RecName: Full=Envelope glycoprotein;
DE   AltName: Full=GP1,2;
DE            Short=GP;
DE   Contains:
DE     RecName: Full=GP1;
DE   Contains:
DE     RecName: Full=GP2;
DE   Contains:
DE     RecName: Full=GP2-delta;
DE   Flags: Precursor;
GN   Name=GP;
OS   Tai Forest ebolavirus (strain Cote d'Ivoire-94) (TAFV) (Cote d'Ivoire Ebola
OS   virus).
OC   Viruses; Riboviria; Orthornavirae; Negarnaviricota; Haploviricotina;
OC   Monjiviricetes; Mononegavirales; Filoviridae; Orthoebolavirus;
OC   Orthoebolavirus taiense; Tai Forest ebolavirus.
OX   NCBI_TaxID=128999;
OH   NCBI_TaxID=77231; Epomops franqueti (Franquet's epauletted fruit bat) (Epomophorus franqueti).
OH   NCBI_TaxID=9606; Homo sapiens (Human).
OH   NCBI_TaxID=77243; Myonycteris torquata (Little collared fruit bat).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA], AND RNA EDITING.
RX   PubMed=8622982; DOI=10.1073/pnas.93.8.3602;
RA   Sanchez A., Trappier S.G., Mahy B.W.J., Peters C.J., Nichol S.T.;
RT   "The virion glycoproteins of Ebola viruses are encoded in two reading
RT   frames and are expressed through transcriptional editing.";
RL   Proc. Natl. Acad. Sci. U.S.A. 93:3602-3607(1996).
RN   [2]
RP   INTERACTION WITH HUMAN CLEC10A.
RX   PubMed=14990712; DOI=10.1128/jvi.78.6.2943-2947.2004;
RA   Takada A., Fujioka K., Tsuiji M., Morikawa A., Higashi N., Ebihara H.,
RA   Kobasa D., Feldmann H., Irimura T., Kawaoka Y.;
RT   "Human macrophage C-type lectin specific for galactose and N-
RT   acetylgalactosamine promotes filovirus entry.";
RL   J. Virol. 78:2943-2947(2004).
CC   -!- FUNCTION: GP1 is responsible for binding to the receptor(s) on target
CC       cells. Interacts with CD209/DC-SIGN and CLEC4M/DC-SIGNR which act as
CC       cofactors for virus entry into the host cell. Binding to CD209 and
CC       CLEC4M, which are respectively found on dendritic cells (DCs), and on
CC       endothelial cells of liver sinusoids and lymph node sinuses, facilitate
CC       infection of macrophages and endothelial cells. These interactions not
CC       only facilitate virus cell entry, but also allow capture of viral
CC       particles by DCs and subsequent transmission to susceptible cells
CC       without DCs infection (trans infection). Binding to the macrophage
CC       specific lectin CLEC10A also seems to enhance virus infectivity.
CC       Interaction with FOLR1/folate receptor alpha may be a cofactor for
CC       virus entry in some cell types, although results are contradictory.
CC       Members of the Tyro3 receptor tyrosine kinase family also seem to be
CC       cell entry factors in filovirus infection. Once attached, the virions
CC       are internalized through clathrin-dependent endocytosis and/or
CC       macropinocytosis. After internalization of the virus into the endosomes
CC       of the host cell, proteolysis of GP1 by two cysteine proteases,
CC       CTSB/cathepsin B and CTSL/cathepsin L presumably induces a
CC       conformational change of GP2, unmasking its fusion peptide and
CC       initiating membranes fusion (By similarity). {ECO:0000250}.
CC   -!- FUNCTION: GP2 acts as a class I viral fusion protein. Under the current
CC       model, the protein has at least 3 conformational states: pre-fusion
CC       native state, pre-hairpin intermediate state, and post-fusion hairpin
CC       state. During viral and target cell membrane fusion, the coiled coil
CC       regions (heptad repeats) assume a trimer-of-hairpins structure,
CC       positioning the fusion peptide in close proximity to the C-terminal
CC       region of the ectodomain. The formation of this structure appears to
CC       drive apposition and subsequent fusion of viral and target cell
CC       membranes. Responsible for penetration of the virus into the cell
CC       cytoplasm by mediating the fusion of the membrane of the endocytosed
CC       virus particle with the endosomal membrane. Low pH in endosomes induces
CC       an irreversible conformational change in GP2, releasing the fusion
CC       hydrophobic peptide (By similarity). {ECO:0000250}.
CC   -!- FUNCTION: [Envelope glycoprotein]: GP1,2 which is the disulfid-linked
CC       complex of GP1 and GP2, mediates endothelial cell activation and
CC       decreases endothelial barrier function. Mediates activation of primary
CC       macrophages. At terminal stages of the viral infection, when its
CC       expression is high, GP1,2 down-modulates the expression of various host
CC       cell surface molecules that are essential for immune surveillance and
CC       cell adhesion. Down-modulates integrins ITGA1, ITGA2, ITGA3, ITGA4,
CC       ITGA5, ITGA6, ITGAV and ITGB1. GP1,2 alters the cellular recycling of
CC       the dimer alpha-V/beta-3 via a dynamin-dependent pathway. Decrease in
CC       the host cell surface expression of various adhesion molecules may lead
CC       to cell detachment, contributing to the disruption of blood vessel
CC       integrity and hemorrhages developed during Ebola virus infection
CC       (cytotoxicity). This cytotoxicity appears late in the infection, only
CC       after the massive release of viral particles by infected cells. Down-
CC       modulation of host MHC-I, leading to altered recognition by immune
CC       cells, may explain the immune suppression and inflammatory dysfunction
CC       linked to Ebola infection. Also down-modulates EGFR surface expression.
CC       Counteracts the antiviral effect of host tetherin (By similarity).
CC       {ECO:0000250|UniProtKB:Q05320}.
CC   -!- FUNCTION: GP2delta is part of the complex GP1,2delta released by host
CC       ADAM17 metalloprotease. This secreted complex may play a role in the
CC       pathogenesis of the virus by efficiently blocking the neutralizing
CC       antibodies that would otherwise neutralize the virus surface
CC       glycoproteins GP1,2. Might therefore contribute to the lack of
CC       inflammatory reaction seen during infection in spite the of extensive
CC       necrosis and massive virus production. GP1,2delta does not seem to be
CC       involved in activation of primary macrophages (By similarity).
CC       {ECO:0000250}.
CC   -!- SUBUNIT: Homotrimer; each monomer consists of a GP1 and a GP2 subunit
CC       linked by disulfide bonds. The resulting peplomers (GP1,2) protrude
CC       from the virus surface as spikes. GP1 and GP2delta are part of
CC       GP1,2delta soluble complexes released by ectodomain shedding. GP1,2
CC       interacts with host integrin ITGAV/alpha-V and CLEC10A. Also binds
CC       human CD209 and CLEC4M (collectively referred to as DC-SIGN(R)), as
CC       well as human FOLR1. Interacts with host entry receptor NPC1.
CC       {ECO:0000250|UniProtKB:Q05320}.
CC   -!- SUBCELLULAR LOCATION: [GP2]: Virion membrane
CC       {ECO:0000250|UniProtKB:Q05320}; Single-pass type I membrane protein
CC       {ECO:0000255}. Host cell membrane {ECO:0000250|UniProtKB:Q05320};
CC       Single-pass type I membrane protein {ECO:0000255}. Note=In the cell,
CC       localizes to the plasma membrane lipid rafts, which probably represent
CC       the assembly and budding site. {ECO:0000250|UniProtKB:Q05320}.
CC   -!- SUBCELLULAR LOCATION: [GP1]: Virion membrane
CC       {ECO:0000250|UniProtKB:Q05320}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:Q05320}. Host cell membrane
CC       {ECO:0000250|UniProtKB:Q05320}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:Q05320}. Note=GP1 is not anchored to the viral
CC       envelope, but forms a disulfid-linked complex with the extravirion
CC       surface GP2. In the cell, both GP1 and GP2 localize to the plasma
CC       membrane lipid rafts, which probably represent the assembly and budding
CC       site. GP1 can also be shed after proteolytic processing.
CC       {ECO:0000250|UniProtKB:Q05320}.
CC   -!- SUBCELLULAR LOCATION: [GP2-delta]: Secreted
CC       {ECO:0000250|UniProtKB:Q05320}. Note=GP2-delta bound to GP1 (GP1,2-
CC       delta) is produced by proteolytic cleavage of GP1,2 by host ADAM17 and
CC       shed by the virus. {ECO:0000250|UniProtKB:Q05320}.
CC   -!- DOMAIN: The mucin-like region seems to be involved in the cytotoxic
CC       function. This region is also involved in binding to human CLEC10A (By
CC       similarity). {ECO:0000250}.
CC   -!- DOMAIN: The coiled coil regions play a role in oligomerization and
CC       fusion activity. {ECO:0000250}.
CC   -!- PTM: The signal peptide region modulates GP's high mannose
CC       glycosylation, thereby determining the efficiency of the interactions
CC       with DC-SIGN(R). {ECO:0000250}.
CC   -!- PTM: N-glycosylated. {ECO:0000250}.
CC   -!- PTM: O-glycosylated in the mucin-like region. {ECO:0000250}.
CC   -!- PTM: Palmitoylation of GP2 is not required for its function.
CC       {ECO:0000250}.
CC   -!- PTM: Specific enzymatic cleavages in vivo yield mature proteins. The
CC       precursor is processed into GP1 and GP2 by host cell furin in the trans
CC       Golgi, and maybe by other host proteases, to yield the mature GP1 and
CC       GP2 proteins. The cleavage site corresponds to the furin optimal
CC       cleavage sequence [KR]-X-[KR]-R. This cleavage does not seem to be
CC       required for function. After the internalization of the virus into cell
CC       endosomes, GP1 C-terminus is removed by the endosomal proteases
CC       cathepsin B, cathepsin L, or both, leaving a 19-kDa N-terminal fragment
CC       which is further digested by cathepsin B. Proteolytic processing of
CC       GP1,2 by host ADAM17 can remove the transmembrane anchor of GP2 and
CC       leads to shedding of complexes consisting in GP1 and truncated GP2
CC       (GP1,2delta) (By similarity). {ECO:0000250}.
CC   -!- RNA EDITING: Modified_positions=295 {ECO:0000269|PubMed:8622982};
CC       Note=Partially edited. RNA editing at this position consists of an
CC       insertion of one adenine nucleotide. The sequence displayed here is the
CC       full-length transmembrane glycoprotein, derived from the edited RNA.
CC       The unedited RNA gives rise to the small secreted glycoprotein (AC
CC       Q66811).;
CC   -!- MISCELLANEOUS: Filoviruses entry requires functional lipid rafts at the
CC       host cell surface. {ECO:0000250}.
CC   -!- MISCELLANEOUS: Essential for infectivity, as it is the sole viral
CC       protein expressed at the virion surface.
CC   -!- SIMILARITY: Belongs to the filoviruses glycoprotein family.
CC       {ECO:0000305}.
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DR   EMBL; U28006; AAB37093.1; -; Genomic_RNA.
DR   BMRB; Q66810; -.
DR   SMR; Q66810; -.
DR   GlyCosmos; Q66810; 10 sites, No reported glycans.
DR   ABCD; Q66810; 1 sequenced antibody.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR   GO; GO:0019031; C:viral envelope; IEA:UniProtKB-KW.
DR   GO; GO:0055036; C:virion membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0075512; P:clathrin-dependent endocytosis of virus by host cell; IEA:UniProtKB-KW.
DR   GO; GO:0098670; P:entry receptor-mediated virion attachment to host cell; IEA:UniProtKB-KW.
DR   GO; GO:0039654; P:fusion of virus membrane with host endosome membrane; IEA:UniProtKB-KW.
DR   GO; GO:0039587; P:suppression by virus of host tetherin activity; IEA:UniProtKB-KW.
DR   GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
DR   CDD; cd09850; Ebola-like_HR1-HR2; 1.
DR   Gene3D; 1.10.287.210; -; 1.
DR   InterPro; IPR014625; GPC_FiloV.
DR   InterPro; IPR002561; GPC_filovir-type_extra_dom.
DR   Pfam; PF01611; Filo_glycop; 1.
DR   PIRSF; PIRSF036874; GPC_FiloV; 1.
DR   SUPFAM; SSF58069; Virus ectodomain; 1.
PE   1: Evidence at protein level;
KW   Clathrin-mediated endocytosis of virus by host;
KW   Cleavage on pair of basic residues; Coiled coil; Disulfide bond;
KW   Fusion of virus membrane with host endosomal membrane;
KW   Fusion of virus membrane with host membrane; Glycoprotein;
KW   Host cell membrane; Host membrane; Host-virus interaction;
KW   Inhibition of host innate immune response by virus;
KW   Inhibition of host tetherin by virus; Lipoprotein; Membrane; Palmitate;
KW   RNA editing; Secreted; Signal; Transmembrane; Transmembrane helix;
KW   Viral attachment to host cell; Viral attachment to host entry receptor;
KW   Viral envelope protein; Viral immunoevasion;
KW   Viral penetration into host cytoplasm; Virion; Virus endocytosis by host;
KW   Virus entry into host cell.
FT   SIGNAL          1..32
FT                   /evidence="ECO:0000255"
FT   CHAIN           33..676
FT                   /note="Envelope glycoprotein"
FT                   /id="PRO_0000037467"
FT   CHAIN           33..501
FT                   /note="GP1"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000037468"
FT   CHAIN           502..676
FT                   /note="GP2"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000037469"
FT   CHAIN           502..637
FT                   /note="GP2-delta"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000245056"
FT   TOPO_DOM        33..650
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        651..671
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        672..676
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   REGION          54..201
FT                   /note="Receptor-binding"
FT                   /evidence="ECO:0000250"
FT   REGION          305..485
FT                   /note="Mucin-like region"
FT                   /evidence="ECO:0000250"
FT   REGION          356..463
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          524..539
FT                   /note="Fusion peptide"
FT                   /evidence="ECO:0000250"
FT   COILED          554..595
FT                   /evidence="ECO:0000255"
FT   COILED          615..634
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        356..387
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        396..462
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            57
FT                   /note="Involved in receptor recognition and/or post-binding
FT                   events"
FT                   /evidence="ECO:0000255"
FT   SITE            63
FT                   /note="Involved in receptor recognition and/or post-binding
FT                   events"
FT                   /evidence="ECO:0000255"
FT   SITE            88
FT                   /note="Involved in receptor recognition and/or post-binding
FT                   events"
FT                   /evidence="ECO:0000255"
FT   SITE            95
FT                   /note="Involved in receptor recognition and/or post-binding
FT                   events"
FT                   /evidence="ECO:0000255"
FT   SITE            170
FT                   /note="Involved in receptor recognition and/or post-binding
FT                   events"
FT                   /evidence="ECO:0000255"
FT   SITE            501..502
FT                   /note="Cleavage; by host furin"
FT                   /evidence="ECO:0000250"
FT   SITE            637..638
FT                   /note="Cleavage; by host ADAM17"
FT                   /evidence="ECO:0000250"
FT   LIPID           670
FT                   /note="S-palmitoyl cysteine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q05320"
FT   LIPID           672
FT                   /note="S-palmitoyl cysteine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q05320"
FT   CARBOHYD        40
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        204
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        228
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        257
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        268
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        296
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        414
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        441
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        563
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        618
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   DISULFID        53..609
FT                   /note="Interchain (between GP1 and GP2 chains)"
FT                   /evidence="ECO:0000250"
FT   DISULFID        108..135
FT                   /evidence="ECO:0000255"
FT   DISULFID        121..147
FT                   /evidence="ECO:0000255"
FT   DISULFID        511..556
FT                   /evidence="ECO:0000255"
FT   DISULFID        601..608
FT                   /evidence="ECO:0000250|UniProtKB:O11457"
SQ   SEQUENCE   676 AA;  74722 MW;  9C753510BFADB48D CRC64;
     MGASGILQLP RERFRKTSFF VWVIILFHKV FSIPLGVVHN NTLQVSDIDK FVCRDKLSST
     SQLKSVGLNL EGNGVATDVP TATKRWGFRA GVPPKVVNYE AGEWAENCYN LAIKKVDGSE
     CLPEAPEGVR DFPRCRYVHK VSGTGPCPGG LAFHKEGAFF LYDRLASTII YRGTTFAEGV
     IAFLILPKAR KDFFQSPPLH EPANMTTDPS SYYHTTTINY VVDNFGTNTT EFLFQVDHLT
     YVQLEARFTP QFLVLLNETI YSDNRRSNTT GKLIWKINPT VDTSMGEWAF WENKKNFTKT
     LSSEELSFVP VPETQNQVLD TTATVSPPIS AHNHAGEDHK ELVSEDSTPV VQMQNIKGKD
     TMPTTVTGVP TTTPSPFPIN ARNTDHTKSF IGLEGPQEDH STTQPAKTTS QPTNSTESTT
     LNPTSEPSSR GTGPSSPTVP NTTESHAELG KTTPTTLPEQ HTAASAIPRA VHPDELSGPG
     FLTNTIRGVT NLLTGSRRKR RDVTPNTQPK CNPNLHYWTA LDEGAAIGLA WIPYFGPAAE
     GIYTEGIMEN QNGLICGLRQ LANETTQALQ LFLRATTELR TFSILNRKAI DFLLQRWGGT
     CHILGPDCCI EPQDWTKNIT DKIDQIIHDF VDNNLPNQND GSNWWTGWKQ WVPAGIGITG
     VIIAIIALLC ICKFML
//