ID   VGP_EBORR               Reviewed;         677 AA.
AC   Q66799; Q5UAK8; Q8JPX8;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   27-MAR-2024, entry version 132.
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=Shed GP;
DE     AltName: Full=GP1,2-delta;
DE   Flags: Precursor;
GN   Name=GP;
OS   Reston ebolavirus (strain Reston-89) (REBOV) (Reston Ebola virus).
OC   Viruses; Riboviria; Orthornavirae; Negarnaviricota; Haploviricotina;
OC   Monjiviricetes; Mononegavirales; Filoviridae; Orthoebolavirus;
OC   Orthoebolavirus restonense; Reston ebolavirus.
OX   NCBI_TaxID=386032;
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).
OH   NCBI_TaxID=9823; Sus scrofa (Pig).
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   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RA   Volchkov V.E.;
RL   Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX   PubMed=12191779; DOI=10.1016/s0168-1702(02)00087-4;
RA   Groseth A., Stroeher U., Theriault S., Feldmann H.;
RT   "Molecular characterization of an isolate from the 1989/90 epizootic of
RT   Ebola virus Reston among macaques imported into the United States.";
RL   Virus Res. 87:155-163(2002).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate Pennsylvania-89;
RX   PubMed=15661171; DOI=10.1016/j.virol.2004.11.018;
RA   Boehmann Y., Enterlein S., Randolf A., Muehlberger E.I.;
RT   "A reconstituted replication and transcription system for Ebola virus
RT   Reston and comparison with Ebola virus Zaire.";
RL   Virology 332:406-417(2005).
RN   [5]
RP   FUNCTION.
RX   PubMed=11836430; DOI=10.1128/jvi.76.5.2518-2528.2002;
RA   Simmons G., Wool-Lewis R.J., Baribaud F., Netter R.C., Bates P.;
RT   "Ebola virus glycoproteins induce global surface protein down-modulation
RT   and loss of cell adherence.";
RL   J. Virol. 76:2518-2528(2002).
CC   -!- FUNCTION: [Envelope glycoprotein]: Trimeric GP1,2 complexes form the
CC       virion surface spikes and mediate the viral entry processes, with GP1
CC       acting as the receptor-binding subunit and GP2 as the membrane fusion
CC       subunit (By similarity). At later times of infection, down-regulates
CC       the expression of various host cell surface molecules that are
CC       essential for immune surveillance and cell adhesion (PubMed:11836430).
CC       Down-modulates several integrins including ITGA1, ITGA2, ITGA3, ITGA4,
CC       ITGA5, ITGA6, ITGAV and ITGB1. This decrease in cell adhesion molecules
CC       may lead to cell detachment, contributing to the disruption of blood
CC       vessel integrity and hemorrhages developed during infection
CC       (cytotoxicity). Interacts with host TLR4 and thereby stimulates the
CC       differentiation and activation of monocytes leading to bystander death
CC       of T-lymphocytes. Down-regulates as well the function of host natural
CC       killer cells. Counteracts the antiviral effect of host BST2/tetherin
CC       that restricts release of progeny virions from infected cells. However,
CC       cooperates with VP40 and host BST2 to activate canonical NF-kappa-B
CC       pathway in a manner dependent on neddylation (By similarity).
CC       {ECO:0000250|UniProtKB:Q05320, ECO:0000269|PubMed:11836430}.
CC   -!- FUNCTION: [Shed GP]: Functions as a decoy for anti-GP1,2 antibodies
CC       thereby contributing to viral immune evasion. Interacts and activates
CC       host macrophages and dendritic cells inducing up-regulation of cytokine
CC       transcription. This effect is mediated throught activation of host
CC       TLR4. {ECO:0000250|UniProtKB:Q05320}.
CC   -!- FUNCTION: [GP1]: 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 dendritic cells (DCs) and endothelial
CC       cells (By similarity). Binding to the macrophage specific lectin
CC       CLEC10A also seems to enhance virus infectivity (By similarity).
CC       Interaction with FOLR1/folate receptor alpha may be a cofactor for
CC       virus entry in some cell types, although results are contradictory (By
CC       similarity). Members of the Tyro3 receptor tyrosine kinase family also
CC       seem to be cell entry factors in filovirus infection (By similarity).
CC       Once attached, the virions are internalized through clathrin-dependent
CC       endocytosis and/or macropinocytosis. After internalization of the virus
CC       into the endosomes of the host cell, proteolysis of GP1 by two cysteine
CC       proteases, CTSB/cathepsin B and CTSL/cathepsin L removes the glycan cap
CC       and allows GP1 binding to the host entry receptor NPC1. NPC1-binding,
CC       Ca(2+) and acidic pH induce a conformational change of GP2, which
CC       unmasks its fusion peptide and permit membranes fusion (By similarity).
CC       {ECO:0000250|UniProtKB:O11457, ECO:0000250|UniProtKB:Q05320,
CC       ECO:0000250|UniProtKB:Q66814}.
CC   -!- FUNCTION: [GP2]: Acts as a class I viral fusion protein. Under the
CC       current model, the protein has at least 3 conformational states: pre-
CC       fusion native state, pre-hairpin intermediate state, and post-fusion
CC       hairpin state. During viral and target cell membrane fusion, the coiled
CC       coil 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. {ECO:0000250|UniProtKB:Q05320}.
CC   -!- SUBUNIT: [Envelope glycoprotein]: Homotrimer; each monomer consists of
CC       a GP1 and a GP2 subunit linked by disulfide bonds. The resulting
CC       peplomers (GP1,2) protrude from the virus surface as spikes. Interacts
CC       with host integrin alpha-V/ITGAV. Interacts with host CLEC10A. Binds
CC       also to host CD209 and CLEC4M/DC-SIGN(R). Interacts with host FOLR1.
CC       Interacts with BST2; this interaction inhibits the antiviral effect of
CC       BST2 and this allows viral release from infected cells. Interacts with
CC       host FCN1; this interaction enhances viral entry. Interacts with host
CC       TLR4; this interaction induces cell death in T-lymphocytes or
CC       proinflammatory cytokines and SOCS1 production in monocytes.
CC       {ECO:0000250|UniProtKB:Q05320}.
CC   -!- SUBUNIT: [GP1]: Interacts with host entry receptor NPC1.
CC       {ECO:0000250|UniProtKB:Q05320}.
CC   -!- SUBUNIT: [Shed GP]: GP1 and GP2delta are part of GP1,2delta soluble
CC       complexes released by ectodomain shedding.
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: [Shed GP]: 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=296 {ECO:0000269|PubMed:8622982};
CC       Note=Partially edited. RNA editing at this position consists of an
CC       insertion of one or two adenine nucleotides. The sequence displayed
CC       here is the full-length transmembrane glycoprotein GP, derived from the
CC       +1A edited RNA. The unedited RNA gives rise to the small secreted
CC       glycoprotein sGP (AC Q66800), the +2A edited RNA gives rise to the
CC       super small secreted glycoprotein ssGP (AC P0C771).;
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; U23152; AAC54885.1; -; Genomic_RNA.
DR   EMBL; AF034645; AAC24346.1; -; Genomic_RNA.
DR   EMBL; AF522874; AAN04455.1; -; Genomic_RNA.
DR   EMBL; AY769362; AAV48577.1; -; Genomic_RNA.
DR   RefSeq; NP_690583.1; NC_004161.1.
DR   SMR; Q66799; -.
DR   GlyCosmos; Q66799; 16 sites, No reported glycans.
DR   ABCD; Q66799; 1 sequenced antibody.
DR   GeneID; 955190; -.
DR   KEGG; vg:955190; -.
DR   Proteomes; UP000007207; Segment.
DR   Proteomes; UP000138664; Genome.
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   3: Inferred from homology;
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..33
FT                   /evidence="ECO:0000255"
FT   CHAIN           34..677
FT                   /note="Envelope glycoprotein"
FT                   /id="PRO_0000037470"
FT   CHAIN           34..502
FT                   /note="GP1"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000037471"
FT   CHAIN           503..677
FT                   /note="GP2"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000037472"
FT   CHAIN           503..638
FT                   /note="Shed GP"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000245061"
FT   TOPO_DOM        34..651
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        652..672
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        673..677
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   REGION          55..202
FT                   /note="Receptor-binding"
FT                   /evidence="ECO:0000250"
FT   REGION          306..486
FT                   /note="Mucin-like region"
FT                   /evidence="ECO:0000250"
FT   REGION          315..349
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          361..484
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          525..540
FT                   /note="Fusion peptide"
FT                   /evidence="ECO:0000250"
FT   COILED          555..596
FT                   /evidence="ECO:0000255"
FT   COILED          616..635
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        315..347
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            58
FT                   /note="Involved in receptor recognition and/or post-binding
FT                   events"
FT                   /evidence="ECO:0000255"
FT   SITE            64
FT                   /note="Involved in receptor recognition and/or post-binding
FT                   events"
FT                   /evidence="ECO:0000255"
FT   SITE            89
FT                   /note="Involved in receptor recognition and/or post-binding
FT                   events"
FT                   /evidence="ECO:0000255"
FT   SITE            96
FT                   /note="Involved in receptor recognition and/or post-binding
FT                   events"
FT                   /evidence="ECO:0000255"
FT   SITE            171
FT                   /note="Involved in receptor recognition and/or post-binding
FT                   events"
FT                   /evidence="ECO:0000255"
FT   SITE            502..503
FT                   /note="Cleavage; by host furin"
FT                   /evidence="ECO:0000250"
FT   SITE            638..639
FT                   /note="Cleavage; by host ADAM17"
FT                   /evidence="ECO:0000250"
FT   LIPID           671
FT                   /note="S-palmitoyl cysteine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q05320"
FT   LIPID           673
FT                   /note="S-palmitoyl cysteine; by host"
FT                   /evidence="ECO:0000250|UniProtKB:Q05320"
FT   CARBOHYD        41
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        205
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        229
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        239
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        258
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        269
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        297
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        317
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        318
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        339
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        406
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        420
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        435
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        463
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        564
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        619
FT                   /note="N-linked (GlcNAc...) asparagine; by host"
FT                   /evidence="ECO:0000255"
FT   DISULFID        54..610
FT                   /note="Interchain (between GP1 and GP2 chains)"
FT                   /evidence="ECO:0000250"
FT   DISULFID        109..136
FT                   /evidence="ECO:0000255"
FT   DISULFID        122..148
FT                   /evidence="ECO:0000255"
FT   DISULFID        512..557
FT                   /evidence="ECO:0000255"
FT   DISULFID        602..609
FT                   /evidence="ECO:0000250|UniProtKB:O11457"
FT   VARIANT         312
FT                   /note="L -> P"
SQ   SEQUENCE   677 AA;  74433 MW;  3D22C37CF856F8BA CRC64;
     MGSGYQLLQL PRERFRKTSF LVWVIILFQR AISMPLGIVT NSTLKATEID QLVCRDKLSS
     TSQLKSVGLN LEGNGIATDV PSATKRWGFR SGVPPKVVSY EAGEWAENCY NLEIKKSDGS
     ECLPLPPDGV RGFPRCRYVH KVQGTGPCPG DLAFHKNGAF FLYDRLASTV IYRGTTFAEG
     VVAFLILSEP KKHFWKATPA HEPVNTTDDS TSYYMTLTLS YEMSNFGGNE SNTLFKVDNH
     TYVQLDRPHT PQFLVQLNET LRRNNRLSNS TGRLTWTLDP KIEPDVGEWA FWETKKNFSQ
     QLHGENLHFQ ILSTHTNNSS DQSPAGTVQG KISYHPPANN SELVPTDSPP VVSVLTAGRT
     EEMSTQGLTN GETITGFTAN PMTTTIAPSP TMTSEVDNNV PSEQPNNTAS IEDSPPSASN
     ETIYHSEMDP IQGSNNSAQS PQTKTTPAPT TSPMTQDPQE TANSSKPGTS PGSAAGPSQP
     GLTINTVSKV ADSLSPTRKQ KRSVRQNTAN KCNPDLYYWT AVDEGAAVGL AWIPYFGPAA
     EGIYIEGVMH NQNGLICGLR QLANETTQAL QLFLRATTEL RTYSLLNRKA IDFLLQRWGG
     TCRILGPSCC IEPHDWTKNI TDEINQIKHD FIDNPLPDHG DDLNLWTGWR QWIPAGIGII
     GVIIAIIALL CICKILC
//