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Sortase

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Sortase family
Pilus-related Sortase C of Group B Streptococcus. PDB entry 3O0P[1]
Identifiers
SymbolSortase
PfamPF04203
InterProIPR005754
SCOP21ija / SCOPe / SUPFAM
OPM superfamily294
OPM protein1rz2
CDDcd00004
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Sortase refers to a group of prokaryotic enzymes that modify surface proteins by recognizing and cleaving a carboxyl-terminal sorting signal. For most substrates of sortase enzymes, the recognition signal consists of the motif LPXTG (Leu-Pro-any-Thr-Gly), then a highly hydrophobic transmembrane sequence, followed by a cluster of basic residues such as arginine. Cleavage occurs between the Thr and Gly, with transient attachment through the Thr residue to the active site Cys residue, followed by transpeptidation that attaches the protein covalently to cell wall components. Sortases occur in almost all Gram-positive bacteria and the occasional Gram-negative bacterium (e.g. Shewanella putrefaciens) or Archaea (e.g. Methanobacterium thermoautotrophicum), where cell wall LPXTG-mediated decoration has not been reported.[2][3] Although sortase A, the "housekeeping" sortase, typically acts on many protein targets, other forms of sortase recognize variant forms of the cleavage motif, or catalyze the assembly of pilins into pili.[4][5][6]

Reaction

The Staphylococcus aureus sortase is a transpeptidase that attaches surface proteins to the cell wall; it cleaves between the Gly and Thr of the LPXTG motif and catalyses the formation of an amide bond between the carboxyl-group of threonine and the amino-group of the cell-wall peptidoglycan.[7][8]

Biological role

Substrate proteins attached to cell walls by sortases include enzymes, pilins, and adhesion-mediating large surface glycoproteins. These proteins often play important roles in virulence, infection, and colonization by pathogens.

Surface proteins not only promote interaction between the invading pathogen and animal tissues, but also provide ingenious strategies for bacterial escape from the host's immune response. In the case of S. aureus protein A, immunoglobulins are captured on the microbial surface and camouflage bacteria during the invasion of host tissues. S. aureus mutants lacking the srtA gene fail to anchor and display some surface proteins and are impaired in the ability to cause animal infections. Sortase acts on surface proteins that are initiated into the secretion (Sec) pathway and have their signal peptide removed by signal peptidase. The S. aureus genome encodes two sets of sortase and secretion genes. It is conceivable that S. aureus has evolved more than one pathway for the transport of 20 surface proteins to the cell wall envelope.

Note that exosortase and archaeosortase are functionally analogous, while not in any way homologous to sortase.[9]

As an antibiotic target

The sortases are thought to be good targets for new antibiotics[10] as they are important proteins for pathogenic bacteria and some limited commercial interest has been noted by at least one company.[11]

Structure

This group of cysteine peptidases belong to MEROPS peptidase family C60 (clan C-) and include the members of several subfamilies of sortases.

Another sub-family of sortases (C60B in MEROPS) contains bacterial sortase B proteins that are approximately 200 residues long.[12]

Use in structural biology

The transpeptidase activity of sortase is taken advantage of by structural biologists to produce fusion proteins in vitro. The recognition motif (LPXTG) is added to the C-terminus of a protein of interest while an oligo-glycine motif is added to the N-terminus of the second protein to be ligated. Upon addition of sortase to the protein mixture, the two peptides are covalently linked through a native peptide bond. This reaction is employed by NMR spectroscopists to produce NMR invisible solubility tags [13] and in one example by X-ray crystallographers to promote complex formation.[14]

See also

References

  1. ^ Cozzi R, Malito E, Nuccitelli A, D'Onofrio M, Martinelli M, Ferlenghi I, Grandi G, Telford JL, Maione D, Rinaudo CD (June 2011). "Structure analysis and site-directed mutagenesis of defined key residues and motives for pilus-related sortase C1 in group B Streptococcus". FASEB Journal. 25 (6): 1874–86. doi:10.1096/fj.10-174797. PMID 21357525.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  2. ^ Mazmanian SK, Ton-That H, Schneewind O (June 2001). "Sortase-catalysed anchoring of surface proteins to the cell wall of Staphylococcus aureus". Molecular Microbiology. 40 (5): 1049–57. CiteSeerX 10.1.1.513.4509. doi:10.1046/j.1365-2958.2001.02411.x. PMID 11401711.
  3. ^ Pallen MJ, Chaudhuri RR, Henderson IR (October 2003). "Genomic analysis of secretion systems". Current Opinion in Microbiology. 6 (5): 519–27. doi:10.1016/j.mib.2003.09.005. PMID 14572546.
  4. ^ Oh SY, Budzik JM, Schneewind O (September 2008). "Sortases make pili from three ingredients". Proceedings of the National Academy of Sciences of the United States of America. 105 (37): 13703–4. Bibcode:2008PNAS..10513703O. doi:10.1073/pnas.0807334105. PMC 2544515. PMID 18784365.
  5. ^ LeMieux J, Woody S, Camilli A (September 2008). "Roles of the sortases of Streptococcus pneumoniae in assembly of the RlrA pilus". Journal of Bacteriology. 190 (17): 6002–13. doi:10.1128/JB.00379-08. PMC 2519520. PMID 18606733.
  6. ^ Kang HJ, Coulibaly F, Proft T, Baker EN (January 2011). Hofmann A (ed.). "Crystal structure of Spy0129, a Streptococcus pyogenes class B sortase involved in pilus assembly". PLOS ONE. 6 (1): e15969. Bibcode:2011PLoSO...615969K. doi:10.1371/journal.pone.0015969. PMC 3019223. PMID 21264317.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ Mazmanian SK, Liu G, Ton-That H, Schneewind O (July 1999). "Staphylococcus aureus sortase, an enzyme that anchors surface proteins to the cell wall". Science. 285 (5428): 760–3. doi:10.1126/science.285.5428.760. PMID 10427003.
  8. ^ Cossart P, Jonquières R (May 2000). "Sortase, a universal target for therapeutic agents against gram-positive bacteria?". Proceedings of the National Academy of Sciences of the United States of America. 97 (10): 5013–5. Bibcode:2000PNAS...97.5013C. doi:10.1073/pnas.97.10.5013. PMC 33977. PMID 10805759.
  9. ^ Haft DH, Payne SH, Selengut JD (January 2012). "Archaeosortases and exosortases are widely distributed systems linking membrane transit with posttranslational modification". Journal of Bacteriology. 194 (1): 36–48. doi:10.1128/JB.06026-11. PMC 3256604. PMID 22037399.
  10. ^ Maresso AW, Schneewind O (March 2008). "Sortase as a target of anti-infective therapy". Pharmacological Reviews. 60 (1): 128–41. doi:10.1124/pr.107.07110. PMID 18321961.
  11. ^ SIGA Technologies (September 2006). "Schedule 14A". U.S. Securities and Exchange Commission. Retrieved 29 October 2009.
  12. ^ Pallen MJ, Lam AC, Antonio M, Dunbar K (March 2001). "An embarrassment of sortases - a richness of substrates?". Trends in Microbiology. 9 (3): 97–102. doi:10.1016/S0966-842X(01)01956-4. PMID 11239768.
  13. ^ Kobashigawa Y, Kumeta H, Ogura K, Inagaki F (March 2009). "Attachment of an NMR-invisible solubility enhancement tag using a sortase-mediated protein ligation method". Journal of Biomolecular NMR. 43 (3): 145–50. doi:10.1007/s10858-008-9296-5. PMID 19140010.
  14. ^ Wang Y, Pascoe HG, Brautigam CA, He H, Zhang X (October 2013). "Structural basis for activation and non-canonical catalysis of the Rap GTPase activating protein domain of plexin". eLife. 2: e01279. doi:10.7554/eLife.01279. PMC 3787391. PMID 24137545.{{cite journal}}: CS1 maint: unflagged free DOI (link)

Further reading

This article incorporates text from the public domain Pfam and InterPro: IPR005754
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