| IED ID | IndEnz0002010799 |
| Enzyme Type ID | protease010799 |
| Protein Name |
Spike glycoprotein S glycoprotein E2 Peplomer protein Cleaved into: Spike protein S1; Spike protein S2; Spike protein S2' |
| Gene Name | S 2 |
| Organism | Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) (SARS-CoV-2) |
| Taxonomic Lineage | Viruses Riboviria Orthornavirae Pisuviricota Pisoniviricetes Nidovirales Cornidovirineae Coronaviridae Orthocoronavirinae Betacoronavirus Sarbecovirus Severe acute respiratory syndrome coronavirus (SARS-CoV) Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) (SARS-CoV-2) |
| Enzyme Sequence | MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT |
| Enzyme Length | 1273 |
| Uniprot Accession Number | P0DTC2 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | FUNCTION: [Spike protein S1]: Attaches the virion to the cell membrane by interacting with host receptor, initiating the infection. Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32221306, PubMed:32075877, PubMed:32155444). Binding to host NRP1 and NRP2 via C-terminal polybasic sequence enhances virion entry into host cell (PubMed:33082294, PubMed:33082293). This interaction may explain virus tropism of human olfactory epithelium cells, which express high level of NRP1 and NRP2 but low level of ACE2 (PubMed:33082293). The stalk domain of S contains three hinges, giving the head unexpected orientational freedom (PubMed:32817270). Uses human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Can be alternatively processed by host furin (PubMed:32362314). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membrane fusion within endosomes. {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:32075877, ECO:0000269|PubMed:32142651, ECO:0000269|PubMed:32155444, ECO:0000269|PubMed:32221306, ECO:0000269|PubMed:32362314, ECO:0000269|PubMed:32817270, ECO:0000269|PubMed:33082293, ECO:0000269|PubMed:33082294, ECO:0000303|PubMed:33082293}.; FUNCTION: [Spike protein S2]: Mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. {ECO:0000255|HAMAP-Rule:MF_04099}.; FUNCTION: [Spike protein S2']: Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis. {ECO:0000255|HAMAP-Rule:MF_04099}.; FUNCTION: [Spike glycoprotein]: May down-regulate host tetherin (BST2) by lysosomal degradation, thereby counteracting its antiviral activity. {ECO:0000250|UniProtKB:P59594}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Beta strand (56); Chain (4); Coiled coil (2); Disulfide bond (15); Domain (2); Glycosylation (26); Helix (26); Lipidation (10); Motif (4); Mutagenesis (29); Natural variant (80); Region (10); Signal peptide (1); Site (2); Topological domain (2); Transmembrane (1); Turn (6) |
| Keywords | 3D-structure;Coiled coil;Disulfide bond;Fusion of virus membrane with host endosomal membrane;Fusion of virus membrane with host membrane;Glycoprotein;Host cell membrane;Host membrane;Host-virus interaction;Inhibition of host innate immune response by virus;Inhibition of host interferon signaling pathway by virus;Inhibition of host tetherin by virus;Lipoprotein;Membrane;Palmitate;Reference proteome;Signal;Superantigen;Transmembrane;Transmembrane helix;Viral attachment to host cell;Viral envelope protein;Viral immunoevasion;Viral penetration into host cytoplasm;Virion;Virulence;Virus entry into host cell |
| Interact With | Itself; A0A1S3APE5; E2DHI3; Q58DD0; Q5EGZ1; Q8R0I0; Q9BYF1; P30530; P35613; Q9NNX6; Q8IUN9; Q8IUN9-2; Q9H2X3; P07711; P00533; P08246; P09958; Q96D42; P11021; P01130; P17931; P47929; O00214; Q61830; P46934-3; O14786; P02776; P31431; P35247; P35247; Q96LC7; Q5EA32; Q9Y5S1; Q9BYF1; P05067 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Virion membrane {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:32979942}; Single-pass type I membrane protein {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:34504087}. Host endoplasmic reticulum-Golgi intermediate compartment membrane {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:34504087}; Single-pass type I membrane protein {ECO:0000255|HAMAP-Rule:MF_04099}. Host cell membrane {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:34504087}; Single-pass type I membrane protein {ECO:0000255|HAMAP-Rule:MF_04099}. Note=Accumulates in the endoplasmic reticulum-Golgi intermediate compartment, where it participates in virus particle assembly. Some S oligomers are transported to the host plasma membrane, where they may mediate cell-cell fusion (PubMed:34504087). An average of 26 +/-15 S trimers are found randomly distributed at the surface of the virion (PubMed:32979942). {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:32979942, ECO:0000269|PubMed:34504087}. |
| Modified Residue | |
| Post Translational Modification | PTM: The cytoplasmic Cys-rich domain is palmitoylated. Palmitoylated spike proteins drive the formation of localized ordered cholesterol and sphingo-lipid-rich lipid nanodomains in the early Golgi, where viral budding occurs. {ECO:0000269|PubMed:34599882}.; PTM: Specific enzymatic cleavages in vivo yield mature proteins. The precursor is processed into S1 and S2 by host CTSL, TMPRSS2 or furin to yield the mature S1 and S2 proteins (PubMed:32155444). CTSL cleavage would occur in endosomes (PubMed:32221306, PubMed:33465165). TMPRSS2 cleavage would occur at the cell surface, allowing the virus to enter the cell despite inhibition of the endosomal pathway by hydroxychloroquine (PubMed:33465165). In addition, a second cleavage results in the release of a fusion peptide upon viral binding to the host cell receptor (By similarity). The polybasic furin cleavage site is absent in SARS-CoV S (PubMed:32155444, PubMed:32362314, PubMed:33465165). It increases the dependence on TMPRSS2 expression by SARS-CoV-2 (PubMed:33465165). D614G substitution would enhance furin cleavage at the S1/S2 junction (PubMed:33417835). {ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:32155444, ECO:0000269|PubMed:32221306, ECO:0000269|PubMed:32362314, ECO:0000269|PubMed:33417835, ECO:0000269|PubMed:33465165}.; PTM: Highly decorated by heterogeneous N-linked glycans protruding from the trimer surface (PubMed:32075877, PubMed:32155444, PubMed:32929138). Highly glycosylated by host both on S1 and S2 subunits, occluding many regions across the surface of the protein (PubMed:32366695, PubMed:32363391, PubMed:32929138). Approximately 40% of the protein surface is shielded from antibody recognition by glycans, with the notable exception of the ACE2 receptor binding domain (PubMed:32929138). {ECO:0000269|PubMed:32075877, ECO:0000269|PubMed:32155444, ECO:0000269|PubMed:32363391, ECO:0000269|PubMed:32366695, ECO:0000269|PubMed:32929138}.; PTM: O-glycosylated by host GALNT1 at the end of S1. This could reduce the efficiency of S1/S2 cleavage. {ECO:0000269|PubMed:34732583}. |
| Signal Peptide | SIGNAL 1..13; /evidence=ECO:0000269|PubMed:34210893 |
| Structure 3D | NMR spectroscopy (3); Electron microscopy (416); X-ray crystallography (176) |
| Cross Reference PDB | 6LVN; 6LXT; 6LZG; 6M0J; 6M17; 6M1V; 6VSB; 6VW1; 6VXX; 6VYB; 6W41; 6WPS; 6WPT; 6X29; 6X2A; 6X2B; 6X2C; 6X6P; 6X79; 6XC2; 6XC3; 6XC4; 6XC7; 6XCM; 6XCN; 6XDG; 6XE1; 6XEY; 6XF5; 6XF6; 6XKL; 6XKP; 6XKQ; 6XLU; 6XM0; 6XM3; 6XM4; 6XM5; 6XR8; 6XRA; 6XS6; 6YLA; 6YM0; 6YOR; 6YZ5; 6YZ7; 6Z2M; 6Z43; 6Z97; 6ZB4; 6ZB5; 6ZBP; 6ZCZ; 6ZDG; 6ZDH; 6ZER; 6ZFO; 6ZGE; 6ZGG; 6ZGI; 6ZH9; 6ZHD; 6ZLR; 6ZOW; 6ZOX; 6ZOY; 6ZOZ; 6ZP0; 6ZP1; 6ZP2; 6ZP5; 6ZP7; 6ZWV; 6ZXN; 7A25; 7A29; 7A4N; 7A5R; 7A5S; 7A91; 7A92; 7A93; 7A94; 7A95; 7A96; 7A97; 7A98; 7AD1; 7AKD; 7B14; 7B17; 7B18; 7B3O; 7B62; 7BEH; 7BEI; 7BEJ; 7BEK; 7BEL; 7BEM; 7BEN; 7BEO; 7BEP; 7BH9; 7BNM; 7BNN; 7BNO; 7BWJ; 7BYR; 7BZ5; 7C01; 7C2L; 7C53; 7C8D; 7C8J; 7C8V; 7C8W; 7CAB; 7CAC; 7CAH; 7CAI; 7CAK; 7CAN; 7CDI; 7CDJ; 7CH4; 7CH5; 7CHB; 7CHC; 7CHE; 7CHF; 7CHH; 7CHO; 7CHP; 7CHS; 7CJF; 7CM4; 7CN4; 7CN9; 7CT5; 7CWL; 7CWM; 7CWN; 7CWO; 7CWS; 7CWT; 7CWU; 7CYH; 7CYP; 7CYV; 7CZP; 7CZQ; 7CZR; 7CZS; 7CZT; 7CZU; 7CZV; 7CZW; 7CZX; 7CZY; 7CZZ; 7D00; 7D03; 7D0B; 7D0C; 7D0D; 7D2Z; 7D30; 7D4G; 7DCC; 7DCX; 7DD2; 7DD8; 7DDD; 7DDN; 7DEO; 7DET; 7DEU; 7DF3; 7DF4; 7DHX; 7DJZ; 7DK0; 7DK3; 7DK4; 7DK5; 7DK6; 7DK7; 7DMU; 7DPM; 7DWX; 7DWY; 7DWZ; 7DX0; 7DX1; 7DX2; 7DX3; 7DX4; 7DX5; 7DX6; 7DX7; 7DX8; 7DX9; 7DZW; 7DZX; 7DZY; 7E23; 7E39; 7E3B; 7E3C; 7E3J; 7E3K; 7E3L; 7E3O; 7E5O; 7E5R; 7E5Y; 7E7B; 7E7D; 7E7X; 7E7Y; 7E86; 7E88; 7E8C; 7E8F; 7E8M; 7EAM; 7EAN; 7EAZ; 7EB0; 7EB3; 7EB4; 7EB5; 7EDF; 7EDG; 7EDH; 7EDI; 7EDJ; 7EH5; 7EJ4; 7EJ5; 7EK6; 7EY0; 7EY4; 7EY5; 7EYA; 7EZV; 7F62; 7F63; 7FDG; 7FDH; 7FDI; 7FDK; 7FG2; 7FG3; 7FG7; 7JJC; 7JJI; 7JJJ; 7JMO; 7JMP; 7JMW; 7JV2; 7JV4; 7JV6; 7JVA; 7JVB; 7JVC; 7JW0; 7JWB; 7JWY; 7JX3; 7JZL; 7JZM; 7JZN; 7JZU; 7K43; 7K45; 7K4N; 7K8M; 7K8S; 7K8T; 7K8U; 7K8V; 7K8W; 7K8X; 7K8Y; 7K8Z; 7K90; 7K9H; 7K9I; 7K9J; 7K9K; 7K9Z; 7KDG; 7KDH; 7KDI; 7KDJ; 7KDK; 7KDL; 7KE4; 7KE6; 7KE7; 7KE8; 7KE9; 7KEA; 7KEB; 7KEC; 7KFV; 7KFW; 7KFX; 7KFY; 7KGJ; 7KGK; 7KJ2; 7KJ3; 7KJ4; 7KJ5; 7KKK; 7KKL; 7KL9; 7KLG; 7KLH; 7KLW; 7KM5; 7KMB; 7KMG; 7KMH; 7KMI; 7KMK; 7KML; 7KMS; 7KMZ; 7KN3; 7KN4; 7KN5; 7KN6; 7KN7; 7KNB; 7KNE; 7KNH; 7KNI; 7KQB; 7KQE; 7KRQ; 7KRR; 7KRS; 7KS9; 7KSG; 7KXJ; 7KXK; 7KZB; 7L02; 7L06; 7L09; 7L0N; 7L2C; 7L2D; 7L2E; 7L2F; 7L3N; 7L4Z; 7L56; 7L57; 7L58; 7L5B; 7L7D; 7L7E; 7L7F; 7L7K; 7LAA; 7LAB; 7LC8; 7LCN; 7LD1; 7LDJ; 7LJR; 7LM8; 7LO4; 7LOP; 7LQ7; 7LQV; 7LQW; 7LRS; 7LRT; 7LS9; 7LSS; 7LWI; 7LWJ; 7LWK; 7LWL; 7LWM; 7LWN; 7LWO; 7LWP; 7LWQ; 7LWS; 7LWT; 7LWU; 7LWV; 7LWW; 7LX5; 7LXW; 7LXX; 7LXY; 7LXZ; 7LY0; 7LY2; 7LY3; 7LYK; 7LYL; 7LYM; 7LYN; 7LYO; 7LYP; 7LYQ; 7M0J; 7M3I; 7M42; 7M53; 7M6D; 7M6E; 7M6F; 7M6G; 7M6H; 7M6I; 7M71; 7M7B; 7M7W; 7M8J; 7M8K; 7M8S; 7M8T; 7M8U; 7MDW; 7ME7; 7MEJ; 7MF1; 7MFU; 7MJG; 7MJH; 7MJI; 7MJJ; 7MJK; 7MJL; 7MJM; 7MJN; 7MKB; 7MKL; 7MKM; 7MLZ; 7MM0; 7MMO; 7MTC; 7MTD; 7MTE; 7MY2; 7MY3; 7MY8; 7MZF; 7MZG; 7MZH; 7MZI; 7MZJ; 7MZK; 7MZL; 7MZM; 7MZN; 7N0G; 7N0H; 7N1A; 7N1B; 7N1E; 7N1F; 7N1Q; 7N1T; 7N1U; 7N1V; 7N1W; 7N1X; 7N1Y; 7N3I; 7N4I; 7N4J; 7N62; 7N64; 7N6D; 7N6E; 7N8H; 7N8I; 7N9A; 7N9B; 7N9C; 7N9E; 7N9T; 7ND3; 7ND4; 7ND5; 7ND6; 7ND7; 7ND8; 7ND9; 7NDA; 7NDB; 7NDC; 7NDD; 7NEG; 7NEH; 7NKT; 7NT9; 7NTA; 7NTC; 7NX6; 7NX7; 7NX8; 7NX9; 7NXA; 7NXB; 7NXC; 7OAN; 7OAO; 7OAP; 7OAQ; 7OAU; 7OAY; 7OLZ; 7OR9; 7ORA; 7ORB; 7P3D; 7P77; 7P78; 7P79; 7P7A; 7P7B; 7R6W; 7R6X; 7R7N; 7R8L; 7R8M; 7R8N; 7R8O; 7R95; 7RA8; 7RAL; 7RKU; 7RKV; 7RNJ; 7RR0; 7RTD; 7RTR; 7RW2; 7RXD; 7S0B; 7S0C; 7S0D; 7S0E; 7S4S; 7V26; 7V2A; 7V76; 7V77; 7V78; 7V79; 7V7A; 7V7D; 7V7E; 7V7F; 7V7G; 7V7H; 7V7I; 7V7J; 7V7N; 7V7O; 7V7P; 7V7Q; 7V7R; 7V7S; 7V7T; 7V7U; 7V7V; 7V7Z; 7V80; 7V81; 7V82; 7V83; 7V84; 7V85; 7V86; 7V87; 7V88; 7V89; 7V8A; 7V8B; 7V8C; |
| Mapped Pubmed ID | 28710774; 32231345; 32239522; 32275855; 32366695; 32404477; 32422645; 32425270; 32454512; 32454513; 32482145; 32511343; 32511354; 32540901; 32571838; 32577631; 32577642; 32577660; 32577661; 32585135; 32587972; 32587975; 32637953; 32637958; 32645326; 32647346; 32661058; 32661423; 32676604; 32694201; 32698192; 32699321; 32703906; 32703908; 32737466; 32737467; 32742241; 32743580; 32753755; 32755598; 32793901; 32793906; 32805734; 32817948; 32887876; 32907861; 32942285; 32958580; 32970990; 32972994; 32991842; 32991844; 32995768; 33020722; 33024963; 33045718; 33052347; 33058755; 33063791; 33082295; 33082574; 33087721; 33149112; 33154106; 33154107; 33154108; 33177651; 33200128; 33242394; 33262452; 33262454; 33271067; 33277323; 33335073; 33381049; 33398270; 33431842; 33431856; 33431876; 33432247; 33436526; 33436577; 33442681; 33442694; 33524990; 33532775; 33579792; 33594361; 33621484; 33655245; 33657135; 33692215; 33707453; 33727252; 33731853; 33737693; 33743891; 33756110; 33758838; 33758863; 33758864; 33761326; 33782529; 33789084; 33794145; 33820835; 33851154; 33852911; 33887205; 33893175; 33893388; 33904225; 33907753; 33914735; 33932326; 33947773; 33958322; 33961621; 33972947; 33974910; 33976198; 33981021; 34015271; 34016740; 34019795; 34021265; 34024246; 34057039; 34086443; 34098567; 34111408; 34135340; 34139176; 34155214; 34161776; 34168070; 34168071; 34210892; 34230894; 34230927; 34234119; 34237283; 34242577; 34242578; 34244522; 34261126; 34273271; 34280951; 34285195; 34302370; 34313527; 34326308; 34329642; 34330908; 34331873; 34338634; 34344823; 34375093; 34384783; 34385690; 34400835; 34433900; 34461095; 34481543; 34534459; 34537245; 34545362; 34548480; 34552091; 34554412; 34563540; 34580306; 34610292; 34620716; 34623907; 34655519; 34685626; 34716452; 34716683; 34930824; |
| Motif | MOTIF 1237..1241; /note="Binding to host endocytosis trafficking protein SNX27"; /evidence="ECO:0000269|PubMed:34504087"; MOTIF 1257..1262; /note="Diacidic ER export motif (host COPII)"; /evidence="ECO:0000269|PubMed:34504087"; MOTIF 1261..1267; /note="Binding to host plasma membrane localising/FERM domain proteins"; /evidence="ECO:0000269|PubMed:34504087"; MOTIF 1269..1273; /note="KxHxx, ER retrieval signal (COPI)"; /evidence="ECO:0000255|HAMAP-Rule:MF_04099, ECO:0000269|PubMed:34504087" |
| Gene Encoded By | |
| Mass | 141,178 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |