P0C0J1 · SPEB_STRP1
- ProteinStreptopain
- GenespeB
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids398 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Cysteine protease that acts as a key streptococcal virulence factor by cleaving host proteins involved in immune response (PubMed:10456871, PubMed:11406581, PubMed:11598100, PubMed:12438337, PubMed:12621045, PubMed:19237546, PubMed:23532847, PubMed:24331465, PubMed:35008838, PubMed:35110732, PubMed:35545676, PubMed:7516997).
Triggers inflammation by mediating cleavage of host proteins, which can both promote host pathogenesis by triggering sterile inflammation and/or restrict streptococcal infection, depending on host immune statue and infection site (PubMed:35008838, PubMed:35110732, PubMed:35545676).
Cleaves host gasdermin-A (GSDMA) in epithelial cells, promoting GSDMA activation and formation of gasdermin pores, triggering pyroptosis (PubMed:35110732, PubMed:35545676).
Pyroptosis triggers the elimination of the infected skin cell, depriving the pathogen of its protective niche, while inducing an inflammatory response (PubMed:35110732, PubMed:35545676).
This ultimately prevents bacterial penetration of the epithelial barrier and a subsequent systemic dissemination of the pathogen (PubMed:35110732, PubMed:35545676).
Also mediates cleavage of the cytokine precursor interleukin-1 beta (IL1B) to its mature form, resulting in inflammation and septic shock (PubMed:28331908, PubMed:32719155).
SpeB-mediated maturation of IL1B plays a dual role depending on infection site: while IL1B inflammatory response prevents bacterial growth during invasive skin infections, it promotes streptococcal infection of the nasopharynx by disrupting colonization resistance mediated by the microbiota (PubMed:28331908, PubMed:32719155).
Inhibits host autophagy be catalyzing cleavage and inactivation of key autophagy factors, such as CALCOCO2, NBR1 and SQSTM1 (PubMed:24331465).
Cleaves and inhibits a number of complement factors, such as C2, C3-beta chain of C3, C4, C5 or SERPING1, thereby promoting evasion of host immunity (PubMed:18160402, PubMed:23532847, PubMed:35008838).
May also impair adaptive immunity by catalyzing cleavage and degradation of host immunoglobulins to promote immune system evasion; the relevance of this activity is however unsure in vivo (PubMed:11406581, PubMed:11598100, PubMed:12438337, PubMed:12496168, PubMed:23569114, PubMed:35008838).
Catalyzes maturation and release of the peptide hormone bradykinin from the precursor Kininogen-1 (KNG1) to produce hypotension during septic shock (PubMed:8760820).
Also involved in bacterial translocation across the host epithelial barrier by mediating cleavage and degradation of host epithelial junction proteins, such as CDH1 and OCLN (PubMed:23532847).
Additionally, has been involved in degradation of fibronectin and vitronectin, two host extracellular matrix proteins involved in tissue integrity (PubMed:7516997).
Also able to catalyze cleavage and degradation of streptococcal proteins, such as C5a peptidase, EndoS or SmeZ (PubMed:16980693, PubMed:18182097, PubMed:24799625, PubMed:7730368).
Degradation of streptococcal proteins is however strictly regulated to preserve integrity of other virulence factors (PubMed:24799625).
Triggers inflammation by mediating cleavage of host proteins, which can both promote host pathogenesis by triggering sterile inflammation and/or restrict streptococcal infection, depending on host immune statue and infection site (PubMed:35008838, PubMed:35110732, PubMed:35545676).
Cleaves host gasdermin-A (GSDMA) in epithelial cells, promoting GSDMA activation and formation of gasdermin pores, triggering pyroptosis (PubMed:35110732, PubMed:35545676).
Pyroptosis triggers the elimination of the infected skin cell, depriving the pathogen of its protective niche, while inducing an inflammatory response (PubMed:35110732, PubMed:35545676).
This ultimately prevents bacterial penetration of the epithelial barrier and a subsequent systemic dissemination of the pathogen (PubMed:35110732, PubMed:35545676).
Also mediates cleavage of the cytokine precursor interleukin-1 beta (IL1B) to its mature form, resulting in inflammation and septic shock (PubMed:28331908, PubMed:32719155).
SpeB-mediated maturation of IL1B plays a dual role depending on infection site: while IL1B inflammatory response prevents bacterial growth during invasive skin infections, it promotes streptococcal infection of the nasopharynx by disrupting colonization resistance mediated by the microbiota (PubMed:28331908, PubMed:32719155).
Inhibits host autophagy be catalyzing cleavage and inactivation of key autophagy factors, such as CALCOCO2, NBR1 and SQSTM1 (PubMed:24331465).
Cleaves and inhibits a number of complement factors, such as C2, C3-beta chain of C3, C4, C5 or SERPING1, thereby promoting evasion of host immunity (PubMed:18160402, PubMed:23532847, PubMed:35008838).
May also impair adaptive immunity by catalyzing cleavage and degradation of host immunoglobulins to promote immune system evasion; the relevance of this activity is however unsure in vivo (PubMed:11406581, PubMed:11598100, PubMed:12438337, PubMed:12496168, PubMed:23569114, PubMed:35008838).
Catalyzes maturation and release of the peptide hormone bradykinin from the precursor Kininogen-1 (KNG1) to produce hypotension during septic shock (PubMed:8760820).
Also involved in bacterial translocation across the host epithelial barrier by mediating cleavage and degradation of host epithelial junction proteins, such as CDH1 and OCLN (PubMed:23532847).
Additionally, has been involved in degradation of fibronectin and vitronectin, two host extracellular matrix proteins involved in tissue integrity (PubMed:7516997).
Also able to catalyze cleavage and degradation of streptococcal proteins, such as C5a peptidase, EndoS or SmeZ (PubMed:16980693, PubMed:18182097, PubMed:24799625, PubMed:7730368).
Degradation of streptococcal proteins is however strictly regulated to preserve integrity of other virulence factors (PubMed:24799625).
Catalytic activity
Activity regulation
Synthesized as an inactive zymogen to protect the intracellular components of the bacteria from proteolytic activity during protein production (By similarity).
Once secreted into the extracellular milieu, cleaved into the active protease: maturation can be mediated in cis by autocatalytic cleavage, or in trans by mature SpeB or host proteases (PubMed:12621045).
Protease activity is strongly inhibited by zinc and copper, which prevent its maturation into an active protease: inhibition by metal ions may be required to prevent proteolysis of streptococcal proteins (PubMed:24799625).
Once secreted into the extracellular milieu, cleaved into the active protease: maturation can be mediated in cis by autocatalytic cleavage, or in trans by mature SpeB or host proteases (PubMed:12621045).
Protease activity is strongly inhibited by zinc and copper, which prevent its maturation into an active protease: inhibition by metal ions may be required to prevent proteolysis of streptococcal proteins (PubMed:24799625).
Features
Showing features for site, active site, binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 53-54 | Cleavage; by autolysis, trypsin and plasmin | ||||
Sequence: KA | ||||||
Site | 57-58 | Cleavage; by host plasmin | ||||
Sequence: RS | ||||||
Site | 68-69 | Cleavage; by autolysis | ||||
Sequence: NL | ||||||
Site | 79-80 | Cleavage; by autolysis | ||||
Sequence: YV | ||||||
Site | 80-81 | Cleavage; by autolysis | ||||
Sequence: VY | ||||||
Site | 84-85 | Cleavage; by autolysis | ||||
Sequence: ST | ||||||
Site | 118-119 | Cleavage; by autolysis | ||||
Sequence: AS | ||||||
Site | 129-130 | Cleavage; by autolysis, trypsin and plasmin | ||||
Sequence: KE | ||||||
Site | 132-133 | Cleavage; by host plasmin | ||||
Sequence: KK | ||||||
Site | 139-140 | Cleavage; by autolysis | ||||
Sequence: AG | ||||||
Site | 145-146 | Cleavage; by autolysis and host trypsin | ||||
Sequence: KQ | ||||||
Site | 150-151 | Cleavage; by host plasmin | ||||
Sequence: KS | ||||||
Active site | 192 | Nucleophile | ||||
Sequence: C | ||||||
Binding site | 282 | a protein (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 339 | a protein (UniProtKB | ChEBI) | ||||
Sequence: G | ||||||
Active site | 340 | Proton acceptor | ||||
Sequence: H |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytosol | |
Cellular Component | extracellular region | |
Cellular Component | host cell cytosol | |
Cellular Component | host extracellular space | |
Molecular Function | cysteine-type endopeptidase activity | |
Molecular Function | toxin activity | |
Biological Process | evasion of host immune response | |
Biological Process | protein maturation | |
Biological Process | proteolysis | |
Biological Process | symbiont-induced defense-related programmed cell death | |
Biological Process | symbiont-mediated suppression of host autophagy |
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameStreptopain
- EC number
- Alternative names
Gene names
Organism names
- Strains
- Taxonomic lineageBacteria > Bacillota > Bacilli > Lactobacillales > Streptococcaceae > Streptococcus
Accessions
- Primary accessionP0C0J1
- Secondary accessions
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Keywords
- Cellular component
Phenotypes & Variants
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | 8 | in strain: 789 | ||||
Sequence: V → I | ||||||
Mutagenesis | 186 | Reduced cysteine protease activity and ability to undergo autocatalytic cleavage. | ||||
Sequence: Q → N | ||||||
Mutagenesis | 192 | Abolished cysteine protease activity and ability to undergo autocatalytic cleavage. Abolished ability to cleave host GSDMA. | ||||
Sequence: C → S | ||||||
Natural variant | 193 | in strain: A-20 | ||||
Sequence: V → L | ||||||
Natural variant | 308 | in strain: 789 | ||||
Sequence: G → S | ||||||
Mutagenesis | 334 | Reduces activity 130-fold. | ||||
Sequence: V → A | ||||||
Mutagenesis | 340 | Abolished cysteine protease activity and ability to undergo autocatalytic cleavage. | ||||
Sequence: H → R | ||||||
Mutagenesis | 356 | Strongly reduced cysteine protease activity and abolished ability to undergo autocatalytic cleavage. | ||||
Sequence: N → D | ||||||
Mutagenesis | 357 | Strongly reduced cysteine protease activity and ability to undergo autocatalytic cleavage. | ||||
Sequence: W → A | ||||||
Mutagenesis | 359 | Reduces activity 420-fold. | ||||
Sequence: W → A | ||||||
Mutagenesis | 384 | Reduces activity 14-fold. | ||||
Sequence: G → D |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 3 variants from UniProt as well as other sources including ClinVar and dbSNP.
PTM/Processing
Features
Showing features for signal, propeptide, chain, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Signal | 1-27 | |||||
Sequence: MNKKKLGVRLLSLLALGGFVLANPVFA | ||||||
Propeptide | PRO_0000041939 | 28-145 | ||||
Sequence: DQNFARNEKEAKDSAITFIQKSAAIKAGARSAEDIKLDKVNLGGELSGSNMYVYNISTGGFVIVSGDKRSPEILGYSTSGSFDANGKENIASFMESYVEQIKENKKLDTTYAGTAEIK | ||||||
Chain | PRO_0000041940 | 146-398 | Streptopain | |||
Sequence: QPVVKSLLDSKGIHYNQGNPYNLLTPVIEKVKPGEQSFVGQHAATGCVATATAQIMKYHNYPNKGLKDYTYTLSSNNPYFNHPKNLFAAISTRQYNWNNILPTYSGRESNVQKMAISELMADVGISVDMDYGPSSGSAGSSRVQRALKENFGYNQSVHQINRGDFSKQDWEAQIDKELSQNQPVYYQGVGKVGGHAFVIDGADGRNFYHVNWGWGGVSDGFFRLDALNPSALGTGGGAGGFNGYQSAVVGIKP | ||||||
Modified residue | 192 | Cysteine methyl disulfide; in zymogen form | ||||
Sequence: C |
Post-translational modification
The mature protease is derived from the precursor sequence by cleavage, either in cis via an autocatalytic mechanism, or in trans by mature SpeB or host proteases (trypsin, plasmin or subtilisin) (PubMed:12621045).
Maturation can involve a number of protein cleavage intermediates (PubMed:12621045).
Mature SpeB probably plays the most important role in protein maturation in physiological conditions (PubMed:12621045).
Maturation can involve a number of protein cleavage intermediates (PubMed:12621045).
Mature SpeB probably plays the most important role in protein maturation in physiological conditions (PubMed:12621045).
Methylthiolation at Cys-192 of the inactive zymogen form is probably involved in the mechanism of secretion of the proteinase into the culture fluid.
Keywords
- PTM
Proteomic databases
Expression
Induction
Expression is regulated by the CovR-CovS two-component regulatory system.
Interaction
Subunit
Monomer.
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 368-390 | C-terminal active site loop | ||||
Sequence: RLDALNPSALGTGGGAGGFNGYQ |
Domain
The C-terminal active site loop is required for the recognition and recruitment of substrates and release of hydrolyzed products.
Sequence similarities
Belongs to the peptidase C10 family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length398
- Mass (Da)43,130
- Last updated2005-09-13 v1
- Checksum4D60DB0B80D687B4
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
L26158 EMBL· GenBank· DDBJ | AAA26987.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF104940 EMBL· GenBank· DDBJ | AAD17930.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AE004092 EMBL· GenBank· DDBJ | AAK34706.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CP000017 EMBL· GenBank· DDBJ | AAZ52353.1 EMBL· GenBank· DDBJ | Genomic DNA |