ID   NS6_SARS                Reviewed;          63 AA.
AC   P59634; Q7T6R9; Q7TA25; Q7TFA7; Q80BV3;
DT   23-APR-2003, integrated into UniProtKB/Swiss-Prot.
DT   23-APR-2003, sequence version 1.
DT   29-MAY-2024, entry version 89.
DE   RecName: Full=ORF6 protein;
DE            Short=ORF6;
DE   AltName: Full=Accessory protein 6;
DE   AltName: Full=Non-structural protein 6;
DE            Short=ns6;
DE   AltName: Full=Protein X3;
GN   ORFNames=6;
OS   Severe acute respiratory syndrome coronavirus (SARS-CoV).
OC   Viruses; Riboviria; Orthornavirae; Pisuviricota; Pisoniviricetes;
OC   Nidovirales; Cornidovirineae; Coronaviridae; Orthocoronavirinae;
OC   Betacoronavirus; Sarbecovirus.
OX   NCBI_TaxID=694009;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
OH   NCBI_TaxID=9675; Paguma larvata (Masked palm civet).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate Urbani;
RX   PubMed=12730500; DOI=10.1126/science.1085952;
RA   Rota P.A., Oberste M.S., Monroe S.S., Nix W.A., Campagnoli R.,
RA   Icenogle J.P., Penaranda S., Bankamp B., Maher K., Chen M.-H., Tong S.,
RA   Tamin A., Lowe L., Frace M., DeRisi J.L., Chen Q., Wang D., Erdman D.D.,
RA   Peret T.C.T., Burns C., Ksiazek T.G., Rollin P.E., Sanchez A., Liffick S.,
RA   Holloway B., Limor J., McCaustland K., Olsen-Rasmussen M., Fouchier R.,
RA   Guenther S., Osterhaus A.D.M.E., Drosten C., Pallansch M.A., Anderson L.J.,
RA   Bellini W.J.;
RT   "Characterization of a novel coronavirus associated with severe acute
RT   respiratory syndrome.";
RL   Science 300:1394-1399(2003).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate Tor2;
RX   PubMed=12730501; DOI=10.1126/science.1085953;
RA   Marra M.A., Jones S.J.M., Astell C.R., Holt R.A., Brooks-Wilson A.,
RA   Butterfield Y.S.N., Khattra J., Asano J.K., Barber S.A., Chan S.Y.,
RA   Cloutier A., Coughlin S.M., Freeman D., Girn N., Griffith O.L., Leach S.R.,
RA   Mayo M., McDonald H., Montgomery S.B., Pandoh P.K., Petrescu A.S.,
RA   Robertson A.G., Schein J.E., Siddiqui A., Smailus D.E., Stott J.M.,
RA   Yang G.S., Plummer F., Andonov A., Artsob H., Bastien N., Bernard K.,
RA   Booth T.F., Bowness D., Czub M., Drebot M., Fernando L., Flick R.,
RA   Garbutt M., Gray M., Grolla A., Jones S., Feldmann H., Meyers A.,
RA   Kabani A., Li Y., Normand S., Stroher U., Tipples G.A., Tyler S.,
RA   Vogrig R., Ward D., Watson B., Brunham R.C., Krajden M., Petric M.,
RA   Skowronski D.M., Upton C., Roper R.L.;
RT   "The genome sequence of the SARS-associated coronavirus.";
RL   Science 300:1399-1404(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate CUHK-Su10, and Isolate CUHK-W1;
RX   PubMed=12853594; DOI=10.1056/nejm200307103490216;
RA   Tsui S.K.W., Chim S.S.C., Lo Y.M.D.;
RT   "Coronavirus genomic-sequence variations and the epidemiology of the severe
RT   acute respiratory syndrome.";
RL   N. Engl. J. Med. 349:187-188(2003).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate HKU-39849;
RX   PubMed=12876307; DOI=10.1177/15353702-0322807-13;
RA   Zeng F.Y., Chan C.W., Chan M.N., Chen J.D., Chow K.Y.C., Hon C.C.C.,
RA   Hui R.K.H., Li J., Li V.Y.Y., Wang C.Y., Wang P.Y., Guan Y., Zheng B.,
RA   Poon L.L.M., Chan K.H., Yuen K.Y., Peiris J.S.M., Leung F.C.;
RT   "The complete genome sequence of severe acute respiratory syndrome
RT   coronavirus strain HKU-39849 (HK-39).";
RL   Exp. Biol. Med. 228:866-873(2003).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate BJ01, Isolate BJ02, Isolate BJ03, Isolate BJ04, and
RC   Isolate GD01;
RA   Qin E., Zhu Q., Yu M., Fan B., Chang G., Si B., Yang B., Peng W., Jiang T.,
RA   Liu B., Deng Y., Liu H., Zhang Y., Wang C., Li Y., Gan Y., Li X., Lu F.,
RA   Tan G., Yang R., Cao W.S., Wang J., Chen W., Cong L., Deng Y., Dong W.,
RA   Han Y., Hu W., Lei M., Li C., Li G., Li G., Li H., Li S., Li S., Li W.,
RA   Li W., Lin W., Liu J., Liu Z., Lu H., Ni P., Qi Q., Sun Y., Tang L.,
RA   Tong Z., Wang J., Wang X., Wu Q., Xi Y., Xu Z., Yang L., Ye C., Ye J.,
RA   Zhang B., Zhang F., Zhang J., Zhang X., Zhou J., Yang H.;
RL   Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate TW1;
RA   Yeh S.-H., Kao C.-L., Tsai C.-Y., Liu C.-J., Chen D.-S., Chen P.-J.;
RT   "The complete genome of SARS coronavirus clone TW1.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate FRA;
RA   Eickmann M., Becker S., Klenk H.-D., Doerr H.W., Stadler K., Censini S.,
RA   Guidotti S., Masignani V., Scarselli M., Mora M., Donati C., Han J.,
RA   Song H.C., Abrignani S., Covacci A., Rappuoli R.;
RT   "SARS virus is a close relative of type II coronaviruses.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate Frankfurt 1;
RA   Thiel V., Hertzig T., Putics A., Ivanov K.A., Schelle B., Bayer S.,
RA   Scheiner B., Weinand H., Weissbrich B., Ziebuhr J.;
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [9]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate Shanghai QXC1;
RA   Yuan Z., Zhang X., Hu Y., Lan S., Wang H., Zhou Z., Wen Y.;
RT   "Analysis of SARS coronavirus genome in Shanghai isolates.";
RL   Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases.
RN   [10]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate Taiwan TC1, Isolate Taiwan TC2, and Isolate Taiwan TC3;
RA   Chang J.-G.C., Lin T.-H., Chen C.-M., Lin C.-S., Chan W.-L., Shih M.-C.;
RL   Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN   [11]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate TWH, Isolate TWJ, Isolate TWK, Isolate TWS, and Isolate TWY;
RA   Shu H.Y., Wu K.M., Tsai S.F.;
RT   "The complete genome of SARS coronavirus TWH.";
RL   Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN   [12]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate HSR 1;
RA   Canducci F., Clementi M., Poli G., Vicenzi E.;
RL   Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN   [13]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC   STRAIN=Isolate AS;
RA   Balotta C., Corvasce S., Violin M., Galli M., Moroni M., Vigevani G.M.,
RA   Ruan Y.J., Salemi M.;
RL   Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN   [14]
RP   SUBCELLULAR LOCATION.
RX   PubMed=16103185; DOI=10.1128/jvi.79.17.11335-11342.2005;
RA   Pewe L., Zhou H., Netland J., Tangudu C., Olivares H., Shi L., Look D.,
RA   Gallagher T., Perlman S.;
RT   "A severe acute respiratory syndrome-associated coronavirus-specific
RT   protein enhances virulence of an attenuated murine coronavirus.";
RL   J. Virol. 79:11335-11342(2005).
RN   [15]
RP   SUBCELLULAR LOCATION.
RC   STRAIN=Isolate CUHK-W1;
RX   PubMed=16310783; DOI=10.1016/j.febslet.2005.11.007;
RA   Geng H., Liu Y.-M., Chan W.S., Lo A.W.-I., Au D.M.-Y., Waye M.M.-Y.,
RA   Ho Y.-Y.;
RT   "The putative protein 6 of the severe acute respiratory syndrome-associated
RT   coronavirus: expression and functional characterization.";
RL   FEBS Lett. 579:6763-6768(2005).
RN   [16]
RP   SUBCELLULAR LOCATION.
RX   PubMed=17108045; DOI=10.1128/jvi.01515-06;
RA   Tangudu C., Olivares H., Netland J., Perlman S., Gallagher T.;
RT   "Severe acute respiratory syndrome coronavirus protein 6 accelerates murine
RT   coronavirus infections.";
RL   J. Virol. 81:1220-1229(2007).
RN   [17]
RP   INTERACTION WITH NSP8, AND SUBCELLULAR LOCATION.
RX   PubMed=17532020; DOI=10.1016/j.virol.2007.04.029;
RA   Kumar P., Gunalan V., Liu B., Chow V.T., Druce J., Birch C., Catton M.,
RA   Fielding B.C., Tan Y.J., Lal S.K.;
RT   "The nonstructural protein 8 (nsp8) of the SARS coronavirus interacts with
RT   its ORF6 accessory protein.";
RL   Virology 366:293-303(2007).
RN   [18]
RP   FUNCTION, INTERACTION WITH HOST KPNA2, AND SUBCELLULAR LOCATION.
RX   PubMed=17596301; DOI=10.1128/jvi.01012-07;
RA   Frieman M., Yount B., Heise M., Kopecky-Bromberg S.A., Palese P.,
RA   Baric R.S.;
RT   "Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1
RT   function by sequestering nuclear import factors on the rough endoplasmic
RT   reticulum/Golgi membrane.";
RL   J. Virol. 81:9812-9824(2007).
RN   [19]
RP   SUBCELLULAR LOCATION, AND MUTAGENESIS OF 49-TYR--LEU-52 AND 53-ASP--GLU-56.
RX   PubMed=22026976; DOI=10.1186/1756-0500-4-446;
RA   Gunalan V., Mirazimi A., Tan Y.J.;
RT   "A putative diacidic motif in the SARS-CoV ORF6 protein influences its
RT   subcellular localization and suppression of expression of co-transfected
RT   expression constructs.";
RL   BMC Res. Notes 4:446-446(2011).
RN   [20]
RP   INTERACTION WITH PROTEIN ORF9B, AND SUBCELLULAR LOCATION.
RX   PubMed=22820404; DOI=10.1016/j.virusres.2012.07.012;
RA   Calvo E., DeDiego M.L., Garcia P., Lopez J.A., Perez-Brena P., Falcon A.;
RT   "Severe acute respiratory syndrome coronavirus accessory proteins 6 and 9b
RT   interact in vivo.";
RL   Virus Res. 169:282-288(2012).
RN   [21]
RP   FUNCTION, INTERACTION WITH HUMAN NUP98-RAE1 COMPLEX, AND MUTAGENESIS OF
RP   MET-58 AND 62-TYR-PRO-63.
RX   PubMed=33849972; DOI=10.1128/mbio.00065-21;
RA   Addetia A., Lieberman N.A.P., Phung Q., Hsiang T.Y., Xie H.,
RA   Roychoudhury P., Shrestha L., Loprieno M.A., Huang M.L., Gale M. Jr.,
RA   Jerome K.R., Greninger A.L.;
RT   "SARS-CoV-2 ORF6 Disrupts Bidirectional Nucleocytoplasmic Transport through
RT   Interactions with Rae1 and Nup98.";
RL   MBio 12:0-0(2021).
RN   [22] {ECO:0007744|PDB:7VPG}
RP   X-RAY CRYSTALLOGRAPHY (2.49 ANGSTROMS) OF 42-63, INTERACTION WITH HOST
RP   RAE1-NUP98, AND MUTAGENESIS OF MET-58.
RX   PubMed=35096974; DOI=10.3389/fmolb.2021.813248;
RA   Li T., Wen Y., Guo H., Yang T., Yang H., Ji X.;
RT   "Molecular mechanism of SARS-CoVs Orf6 targeting the Rae1-Nup98 complex to
RT   compete with mRNA nuclear export.";
RL   Front. Mol. Biosci. 8:813248-813248(2022).
CC   -!- FUNCTION: Disrupts bidirectional nucleocytoplasmic transport by
CC       interacting with host RAE1-NUP98 complex (PubMed:33849972). Disrupts
CC       cell nuclear import complex formation also by tethering karyopherin
CC       alpha 2 and karyopherin beta 1 to the membrane (PubMed:17596301).
CC       Retention of import factors at the ER/Golgi membrane leads to a loss of
CC       transport into the nucleus (PubMed:17596301). Thereby prevents STAT1
CC       nuclear translocation in response to interferon signaling, thus
CC       blocking the expression of interferon stimulated genes (ISGs) that
CC       display multiple antiviral activities (PubMed:17596301).
CC       {ECO:0000269|PubMed:17596301, ECO:0000269|PubMed:33849972}.
CC   -!- SUBUNIT: May interact with nsp8 (PubMed:17532020). Interacts with
CC       protein ORF9b (PubMed:22820404). Interacts with host RAE1 in NUP98-RAE1
CC       complex (PubMed:35096974); the interaction disrupts the host nuclear
CC       import (PubMed:33849972). Interacts with host KPNA2 (PubMed:17596301).
CC       {ECO:0000269|PubMed:17532020, ECO:0000269|PubMed:17596301,
CC       ECO:0000269|PubMed:22820404, ECO:0000269|PubMed:33849972,
CC       ECO:0000269|PubMed:35096974}.
CC   -!- INTERACTION:
CC       P59634; Q13561: DCTN2; Xeno; NbExp=2; IntAct=EBI-25489038, EBI-715074;
CC       P59634; Q92617: NPIPB3; Xeno; NbExp=3; IntAct=EBI-25489038, EBI-2866234;
CC       P59634; P52948: NUP98; Xeno; NbExp=6; IntAct=EBI-25489038, EBI-295727;
CC   -!- SUBCELLULAR LOCATION: Host endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:17108045, ECO:0000269|PubMed:17532020,
CC       ECO:0000269|PubMed:17596301}. Host Golgi apparatus membrane
CC       {ECO:0000269|PubMed:17108045, ECO:0000269|PubMed:17596301}. Host
CC       cytoplasm {ECO:0000269|PubMed:22820404}. Note=Localizes to virus-
CC       induced vesicular structures called double membrane vesicles.
CC       {ECO:0000269|PubMed:17108045, ECO:0000269|PubMed:17596301,
CC       ECO:0000269|PubMed:22026976}.
CC   -!- SIMILARITY: Belongs to the coronaviruses accessory protein 6 family.
CC       {ECO:0000305}.
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DR   EMBL; AY278741; AAP13448.1; -; Genomic_RNA.
DR   EMBL; AY274119; AAP41042.1; -; Genomic_RNA.
DR   EMBL; AY282752; -; NOT_ANNOTATED_CDS; Genomic_RNA.
DR   EMBL; AY278554; AAP13572.1; -; Genomic_RNA.
DR   EMBL; AY278491; -; NOT_ANNOTATED_CDS; Genomic_RNA.
DR   EMBL; AY278487; -; NOT_ANNOTATED_CDS; Genomic_RNA.
DR   EMBL; AY278488; AAP30035.1; -; Genomic_RNA.
DR   EMBL; AY278489; AAP51232.1; -; Genomic_RNA.
DR   EMBL; AY278490; -; NOT_ANNOTATED_CDS; Genomic_RNA.
DR   EMBL; AY279354; -; NOT_ANNOTATED_CDS; Genomic_RNA.
DR   EMBL; AY291451; AAP37022.1; -; Genomic_RNA.
DR   EMBL; AY310120; AAP50490.1; -; Genomic_RNA.
DR   EMBL; AY291315; AAP33702.1; -; Genomic_RNA.
DR   EMBL; AY463059; AAR86791.1; -; Genomic_RNA.
DR   EMBL; AY338174; AAQ01602.1; -; Genomic_RNA.
DR   EMBL; AY338175; AAQ01614.1; -; Genomic_RNA.
DR   EMBL; AY348314; AAP97887.1; -; Genomic_RNA.
DR   EMBL; AP006557; BAC81353.1; -; Genomic_RNA.
DR   EMBL; AP006558; BAC81367.1; -; Genomic_RNA.
DR   EMBL; AP006559; BAC81381.1; -; Genomic_RNA.
DR   EMBL; AP006560; BAC81395.1; -; Genomic_RNA.
DR   EMBL; AP006561; BAC81409.1; -; Genomic_RNA.
DR   EMBL; AY323977; AAP72979.1; -; Genomic_RNA.
DR   EMBL; AY427439; AAQ94065.1; -; Genomic_RNA.
DR   PDB; 7F90; X-ray; 2.39 A; E/F=1-63.
DR   PDB; 7VPG; X-ray; 2.49 A; I/J/K/X=42-63.
DR   PDBsum; 7F90; -.
DR   PDBsum; 7VPG; -.
DR   SMR; P59634; -.
DR   BioGRID; 4383919; 25.
DR   IntAct; P59634; 13.
DR   MINT; P59634; -.
DR   OrthoDB; 40904at10239; -.
DR   Reactome; R-HSA-9692916; SARS-CoV-1 activates/modulates innate immune responses.
DR   SIGNOR; P59634; -.
DR   Proteomes; UP000000354; Segment.
DR   Proteomes; UP000103670; Genome.
DR   Proteomes; UP000109640; Genome.
DR   Proteomes; UP000116947; Genome.
DR   Proteomes; UP000121636; Genome.
DR   Proteomes; UP000131569; Genome.
DR   Proteomes; UP000131955; Genome.
DR   Proteomes; UP000137377; Genome.
DR   Proteomes; UP000138690; Genome.
DR   Proteomes; UP000143093; Genome.
DR   Proteomes; UP000145651; Genome.
DR   Proteomes; UP000146108; Genome.
DR   Proteomes; UP000146181; Genome.
DR   Proteomes; UP000146296; Genome.
DR   Proteomes; UP000148194; Genome.
DR   Proteomes; UP000153467; Genome.
DR   Proteomes; UP000160648; Genome.
DR   Proteomes; UP000164441; Genome.
DR   Proteomes; UP000172416; Genome.
DR   GO; GO:0044167; C:host cell endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0044178; C:host cell Golgi membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR   GO; GO:0039563; P:symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity; IEA:UniProtKB-KW.
DR   GO; GO:0039502; P:symbiont-mediated suppression of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
DR   GO; GO:0019049; P:virus-mediated perturbation of host defense response; IEA:UniProtKB-KW.
DR   InterPro; IPR022736; NS6_bCoV.
DR   Pfam; PF12133; bCoV_NS6; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Host cytoplasm; Host endoplasmic reticulum;
KW   Host Golgi apparatus; Host membrane; Host-virus interaction;
KW   Inhibition of host innate immune response by virus;
KW   Inhibition of host interferon signaling pathway by virus;
KW   Inhibition of host STAT1 by virus; Interferon antiviral system evasion;
KW   Membrane; Reference proteome; Viral immunoevasion; Virulence.
FT   CHAIN           1..63
FT                   /note="ORF6 protein"
FT                   /id="PRO_0000106134"
FT   REGION          54..63
FT                   /note="Critical for disrupting nuclear import"
FT                   /evidence="ECO:0000269|PubMed:17596301"
FT   VARIANT         32..63
FT                   /note="IISSIVRQLFKPLTKKNYSELDDEEPMELDYP -> NKFNSETII (in
FT                   strain: Isolate TWJ)"
FT   VARIANT         57
FT                   /note="P -> L (in strain: Isolate GD01, Isolate BJ01,
FT                   Isolate BJ02, Isolate BJ03 and Isolate BJ04)"
FT   MUTAGEN         49..52
FT                   /note="YSEL->AAAA: No effect in the suppression of nuclear
FT                   gene expression."
FT                   /evidence="ECO:0000269|PubMed:22026976"
FT   MUTAGEN         53..56
FT                   /note="DDEE->AAAA: Reduction in the suppression of nuclear
FT                   gene expression."
FT                   /evidence="ECO:0000269|PubMed:22026976"
FT   MUTAGEN         58
FT                   /note="M->A: Decreases down-regulation of protein
FT                   expression of newly transcribed genes in the host cell.
FT                   Complete loss of RAE1 binding."
FT                   /evidence="ECO:0000269|PubMed:33849972,
FT                   ECO:0000269|PubMed:35096974"
FT   MUTAGEN         62..63
FT                   /note="Missing: Decreases down-regulation of protein
FT                   expression of newly transcribed genes in the host cell."
FT                   /evidence="ECO:0000269|PubMed:33849972"
SQ   SEQUENCE   63 AA;  7527 MW;  70C9150941C759BF CRC64;
     MFHLVDFQVT IAEILIIIMR TFRIAIWNLD VIISSIVRQL FKPLTKKNYS ELDDEEPMEL
     DYP
//