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SARS-CoV-2 Relevant PROSITE Motifs

Sigrist CJA, Bridge A, Le Mercier P.
A potential role for integrins in host cell entry by SARS-CoV-2.
Antiviral Res. 2020 Mar 1;177:104759. doi: 10.1016/j.antiviral.2020.104759.
PubMed: 32130973 [Full text] [PDF version]

Profiles detected in SARS-CoV-2 proteins

Their associated ProRule provide additional information used to increase the discriminatory power and to annotate UniProtKB/Swiss-Prot proteins.

Macro domain profile (PS51154)

The Macro or A1pp domain is a module of ~180 amino acids which can bind ADP-ribose, an NAD metabolite or related ligands. The Macro domain has been suggested to play a regulatory role in ADP-ribosylation, which is involved in inter- and intracellular signaling, transcriptional regulation, DNA repair pathways and maintenance of genomic stability, telomere dynamics, cell differentiation and proliferation, and necrosis and apoptosis. Viral Macro domains reverse protein ADP-ribosylation.

Peptidase family C16 domain profile (PS51124)

Peptidase family C16 (EC 3.4.22.-) contains the coronaviruses accessory cysteine proteinases that recognize and process one or two sites in the amino-terminal half of the replicase polyprotein during assembly of the viral replication complex. The SARS-CoV-2 papain-like protease (PL-PRO) belongs to this family.

Coronavirus main protease (M-pro) domain profile (PS51442)

The maturation of coronaviruses involves a highly complex cascade of proteolytic processing events on the polyproteins to control viral gene expression and replication. Most maturation cleavage events within the precursor polyprotein are mediated by a viral cysteine proteinase which is called the 'main proteinase' (M-pro) or, alternatively, the '3C-like proteinase' (3CL-pro). The ~300-residue mature form of the M-pro is released from pp1a and pp1ab by autoproteolytic cleavage and employs conserved cysteine and histidine residues in the catalytic site.

RdRp of positive ssRNA viruses catalytic domain profile (PS50507)

RNA-directed RNA polymerase (RdRp) (EC is an essential protein encoded in the genomes of all RNA containing viruses with no DNA stage. It catalyses synthesis of the RNA strand complementary to a given RNA template.

Coronaviridae zinc-binding (CV ZBD) domain profile (PS51653)

The coronavirus nsp13 protein is comprised of a C-terminal nucleoside triphosphate-binding/helicase (Hel) motif and an N-terminal cysteine-rich zinc-binding domain (ZBD). The ZBD is critically involved in coronavirus replication and transcription by modulating the enzymatic activities of the helicase domain and other, yet unknown, mechanisms.

(+)RNA virus helicase core domain profile (PS51657)

Implicated in diverse aspects of transcription and replication.

Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal and C-terminal domain (NTD and CTD) profiles (PS51921 and PS51922)

The S protein, which is located on the envelope surface of the virion, functions to mediate receptor recognition and membrane fusion and is therefore a key factor determining the virus tropism for a specific species. In most cases, coronaviral S will be further cleaved into S1 and S2 subunits, and the receptor binding capacity is allocated to the S1 subunit. The receptor binding domain (RBD) of betaCoV that directly engages the receptor is commonly located in the C-terminal half of S1 [C-terminal domain (CTD)] such as in SARS-CoV,SARS-CoV-2, MERS-CoV, and BatCoV HKU4, though in rare cases such as with mouse hepatitis virus (MHV), the RBD region was identified in the S1 N-terminal domain (NTD).

Sarbecovirus 9b domain profile (PS51920)

p9b could have a role in membrane interactions during the assembly of the virus.

X4e domain profile (PS51919)

The Sarbecovirus accessory protein X4, also called 7a or U122, is likely to be a type I membrane protein, with the amino-terminal hydrophilic domain oriented inside the lumen of the ER/Golgi or on the surface of the cell membrane or virus particle, depending on the localization of the protein. It has been suggested that X4e contains a binding site for the alpha(L) integrin subunit I-domain of LFA-1.

Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) and 2 (HR2) regions profiles (PS51923 and PS51924)

The S protein, which is located on the envelope surface of the virion, functions to mediate receptor recognition and membrane fusion and is therefore a key factor determining the virus tropism for a specific species. This protein is composed of an N-terminal receptor-binding domain (S1) and a C-terminal trans-membrane fusion domain (S2). The S2 subunit contains two 4-3 heptad repeats (HRs) of hydrophobic residues, HR1 and HR2, typical of coiled coils, separated by an ~170-aa-long intervening domain. The S2 subunit is expected to present rearrangement of its HRs to form a stable 6-helix bundle fusion core.

New profiles (not yet public) detected in SARS-CoV-2 proteins

They are not yet publicly available but their associated ProRule are already used to annotate UniProtKB/Swiss-Prot proteins.

Coronavirus envelope (CoV E) protein profile (PS51926)

Coronavirus envelope (CoV E) proteins are involved in several aspects of the virus' life cycle, such as assembly, budding, envelope formation, and pathogenesis. They are ~100-residue-long polypeptides that are minor components in virions but are abundantly expressed inside infected cells. They are localized mainly to the endoplasmic reticulum (ER) and Golgi-complex where they participate in the assembly, budding, and intracellular trafficking of infectious virions.

Coronavirus membrane (CoV M) protein profile (PS51927)

The Coronavirus membrane (CoV M) protein, which functions as a homodimer, adapts a region of membrane for virus assembly and captures other structural proteins at the budding site.

Coronavirus nucleocapsid (CoV N) protein N- and C-terminal (NTD and CTD) domains profiles (PS51928 and PS51929)

The coronavirus nucleocapsid (CoV N) protein serves multiple purposes, such as packaging the RNA genome into helical ribonucleoproteins, modulating host cell metabolism, and regulating viral RNA synthesis during replication and transcription. CoV N proteins contain two structured domains: the N-terminal domain (NTD; also called RBD), which is responsible for RNA binding, and the C-terminal domain (CTD; also called DD), which mediates oligomerization and RNA binding.

Patterns with a high probability of occurrence detected in SARS-CoV-2 proteins

They have poor specificity and generate many false positives. Their matches are reviewed by expert curators before inclusion in UniProtKB/Swiss-Prot.

Cell attachment sequence (PS00016)

The spike protein of SARS-CoV-2 acquired a RGD motif known to bind integrins. This motif is absent from other coronaviruses.

N-glycosylation site (PS00001)

The SARS-CoV-2 viral envelope comprises of three proteins where spike (S) and membrane (M) are the two major glycoproteins and envelope (E) is the non-glycosylated protein. N-glycosylation sites are specific to the consensus sequence Asn-Xaa-Ser/Thr. This signature performs well to detect potential N-glycosylation sites of extracellular viral proteins.