Biology:Parvulin-like peptidyl-prolyl isomerase

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Short description: Functions as a molecular chaperone in Gram-positive bacteria

Parvulin-like peptidyl-prolyl isomerase (PrsA), also referred to as putative proteinase maturation protein A (PpmA), functions as a molecular chaperone in Gram-positive bacteria, such as B. subtilis, S. aureus, L. monocytogenes and S. pyogenes. PrsA proteins contain a highly conserved parvulin domain that contains peptidyl-prolyl cis-trans isomerase (PPIase) activity capable of catalyzing the bond N-terminal to proline from cis to trans, or vice versa, which is a rate limiting step in protein folding.[1] PrsA homologs also contain a foldase domain suspected to aid in the folding of proteins but, unlike the parvulin domain, is not highly conserved.[2] PrsA proteins are capable of forming multimers in vivo and in vitro and, when dimerized, form a claw-like structure linked by the NC domains.[2][3] Most Gram-positive bacteria contain only one PrsA-like protein, but some organisms such as L. monocytogenes, B. anthracis and S. pyogenes contain two PrsAs.

Function

In B. subtilis, PrsA is generally well characterized compared to PrsA homologs in other Gram-positive organisms. Secreteomic analyses have shown the absence of PrsA significantly impacts the yield of secreted proteins and that it is required for normal growth.[2][4] In L. monocytogenes, there is a 5-6 log decrease in virulence when only one of two PrsA genes are deleted in a murine mouse model.[5] Furthermore, PrsA-depleted bacterial cells have a decreased resistance to antibiotics, potentially due to its involvement in cell wall biogenesis, and thus PrsA may serve an antimicrobial target.[6][7]

There is evidence to support that parvulins, such as PrsA homologs, in Gram-positive bacteria function to fold and stabilize secreted proteins.[8] Current data suggests that they are secreted from the cytoplasm to function in the interface between the cell wall and bacterial membrane. Here, they become tethered to the bacterial membrane via lipidation and mutation of the residue that lipidates PrsA to the bacterial membrane results in monomeric units, whereas when it is not mutated PrsA dimerizes and the dimer form is important for its function.[2][3][4]

Virulence factors are primarily secreted out of the Sec translocation pathway in an unfolded state and must fully fold to function in pathogenesis. The role of PrsA proteins have been implicated in aiding in protein folding of those unfolded secreted proteins to promote virulence. Additionally, PrsA function has been implicated in full biofilm formation, swimming motility, stress resistance as well as other biological processes.[5][9][10][11][12]

References

  1. ↑ Scheuplein, N (2020). "Targeting Protein Folding: A Novel Approach for the Treatment of Pathogenic Bacteria". Journal of Medical Chemistry 63 (22): 13355–13388. doi:10.1021/acs.jmedchem.0c00911. PMID 32786507. 
  2. ↑ 2.0 2.1 2.2 2.3 Jakob, Roman P. (February 6, 2015). "Dimeric Structure of the Bacterial Extracellular Foldase PrsA". The Journal of Biological Chemistry 290 (6): 3278–3292. doi:10.1074/jbc.M114.622910. PMID 25525259. 
  3. ↑ 3.0 3.1 Cahoon, Laty A. (2016). "A structural comparison ofListeria monocytogenesproteinchaperones PrsA1 and PrsA2 reveals molecular featuresrequired for virulence". Molecular Microbiology 101 (1): 42–61. doi:10.1111/mmi.13367. PMID 27007641. 
  4. ↑ 4.0 4.1 Kontinen, Vesa P. (1993). "737The PrsA lipoprotein is essential for protein secretion inBacillus subtilis and sets a limit for high-level secretion". Molecular Microbiology 8 (4): 727–737. doi:10.1111/j.1365-2958.1993.tb01616.x. PMID 8332065. 
  5. ↑ 5.0 5.1 Alonzo III, Francis (July 2009). "The Posttranslocation Chaperone PrsA2 Contributes to MultipleFacets ofListeria monocytogenesPathogenesis". Infection and Immunity 77 (7): 2612–2623. doi:10.1128/IAI.00280-09. PMID 19451247. 
  6. ↑ Hyyrylainen, Hanne-Leena (2010). "Penicillin-binding protein folding is dependent on the PrsApeptidyl-prolylcis-transisomerase inBacillus subtilis". Molecular Microbiology 77 (1): 108–127. doi:10.1111/j.1365-2958.2010.07188.x. PMID 20487272. 
  7. ↑ Alonzo III, Francis (2011). "Functional analysis of theListeria monocytogenessecretion chaperone PrsA2 and its multiple contributions tobacterial virulence". Molecular Microbiology 80 (6): 1530–1548. doi:10.1111/j.1365-2958.2011.07665.x. PMID 21545417. 
  8. ↑ Sarvas, Matti (November 11, 2004). "Post-translocational folding of secretory proteins in Gram-positive bacteria". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1694 (1–3): 311–327. doi:10.1016/j.bbamcr.2004.04.009. PMID 15546674. 
  9. ↑ Guo, Lihong (April 29, 2013). "Phenotypic characterization of the foldase homologue PrsA in Streptococcus mutans". Mol Oral Microbiology 28 (2): 154–165. doi:10.1111/omi.12014. PMID 23241367. 
  10. ↑ Cahoon, Laty A. (October 2015). "dentification of Conserved and Species-Specific Functions of theListeria monocytogenes PrsA2 Secretion Chaperone". Infection and Immunity 83 (10): 4028–4041. doi:10.1128/IAI.00504-15. PMID 26216425. 
  11. ↑ Alonzo III, Francis (November 2010). "Listeria monocytogenesPrsA2 Is Required for Virulence FactorSecretion and Bacterial Viability within the Host Cell Cytosol". Infection and Immunity 78 (11): 4944–4957. doi:10.1128/IAI.00532-10. PMID 20823208. 
  12. ↑ Zemansky, Jason (June 2009). "Development of amariner-Based Transposon and Identification of Listeria monocytogenes Determinants, Including the Peptidyl-ProlylIsomerase PrsA2, That Contribute to Its Hemolytic Phenotype". Journal of Bacteriology 191 (12): 3950–3964. doi:10.1128/JB.00016-09. PMID 19376879. 



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