Subsystem: Sortase

This subsystem's description is:

Sortases promote the covalent anchoring of surface proteins to the cell wall envelope. These enzymes catalyze a transpeptidation reaction by first cleaving a surface protein substrate at the cell wall sorting signal. The resulting acyl enzyme intermediates between sortases and their substrates are then resolved by the nucleophilic attack of amino groups, typically provided by the cell wall cross bridges of peptidoglycan precursors. The product of the sortase reaction, a surface protein linked to peptidoglycan, is then incorporated into the envelope and displayed on the microbial surface. Surface proteins typically carry two topogenic sequences, N-terminal signal peptides and C-terminal sorting signals. Cell wall sorting signals span approximately 30 to 40 residues and comprise a short pentapeptide motif followed by a stretch of hydrophobic side chains and finally a mostly positively charged tail at the C-terminal end of the polypeptide.
Sortase is a central factor in the so-called "sorting pathway." This pathway begins with the synthesis of a surface protein precursor in the cytoplasm. The N-terminal signal peptide then directs the precursor to the membrane for translocation. Once the signal peptide has been cleaved and the polypeptide is moved across the plasma membrane, the cell wall sorting signal functions to retain the polypeptide within the secretory pathway. Membrane-anchored sortases cleave sorting signals at their pentapeptide motif and promote anchoring to the cell wall.

For more information, please check out the description and the additional notes tabs, below

Literature ReferencesSortases and the art of anchoring proteins to the envelopes of gram-positive bacteria. Marraffini LA Microbiology and molecular biology reviews : MMBR 2006 Mar16524923
A comparative genome analysis identifies distinct sorting pathways in gram-positive bacteria. Comfort D Infection and immunity 2004 May15102780
Pili in Gram-positive bacteria: assembly, involvement in colonization and biofilm development. Mandlik A Trends in microbiology 2008 Jan18083568
DiagramFunctional RolesSubsystem SpreadsheetDescriptionAdditional Notes 

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IsdAAPAP_FPAP_LP*SrtA*SrtBSrtC
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Sortases promote the covalent anchoring of surface proteins to the cell wall envelope. These enzymes catalyze a transpeptidation reaction by first cleaving a surface protein substrate at the cell wall sorting signal. The resulting acyl enzyme intermediates between sortases and their substrates are then resolved by the nucleophilic attack of amino groups, typically provided by the cell wall cross bridges of peptidoglycan precursors. The product of the sortase reaction, a surface protein linked to peptidoglycan, is then incorporated into the envelope and displayed on the microbial surface. Surface proteins typically carry two topogenic sequences, N-terminal signal peptides and C-terminal sorting signals. Cell wall sorting signals span approximately 30 to 40 residues and comprise a short pentapeptide motif followed by a stretch of hydrophobic side chains and finally a mostly positively charged tail at the C-terminal end of the polypeptide.
Sortase is a central factor in the so-called "sorting pathway." This pathway begins with the synthesis of a surface protein precursor in the cytoplasm. The N-terminal signal peptide then directs the precursor to the membrane for translocation. Once the signal peptide has been cleaved and the polypeptide is moved across the plasma membrane, the cell wall sorting signal functions to retain the polypeptide within the secretory pathway. Membrane-anchored sortases cleave sorting signals at their pentapeptide motif and promote anchoring to the cell wall.
Sortase and sortase-like genes have been found in almost all gram-positive bacterial genomes. Additionally, sortase enzymes have been identified in the gram-negative organisms Bradyrhizobium japonicum, Colwellia psychroerythraea, Microbulbifer degradans, Shewanella oneidensis, and Shewanella putrefasciens, as well as in Methanobacterium thermoautotrophicum, a thermophilic archaeon. Interestingly, in the majority of genomes where sortase enzyme genes have been identified, usually multiple sortases are encoded.

Based on homology, the sortases thus far identified can be grouped into six subgroups or classes:

two of the gram-positive subfamilies are called SrtA and SrtB, since their members have primary sequences that are most closely related to the well-characterized SrtA and SrtB proteins from S. aureus. The remaining gram-positive subfamilies are numbered 3, 4, and 5, whereas the gram-negative subfamily is also known as subfamily 6. Each subgroup, in addition to distinctions in sequence, can be distinguished from one another based on membrane topology, genome position, and preference for substrates with specific amino acids within the cell wall sorting signal pentapeptide motif:

----Sortase A-------

The prototypical sortase A, first identified in S. aureus, contains an N-terminal transmembrane domain and the sequence TLXTC at its active site, where C corresponds to the catalytic cysteine residue (Cys184 in S. aureus sortase A). Sortase A appears to anchor a large number and broad range of surface proteins, and unlike many other sortase genes, the sortase A gene is not found clustered with its substrates. It also appears that only a single sortase A homolog is encoded per bacterial genome. The sortase A subgroup of enzymes also seems to share a preference for the LPXTG cell wall sorting signal motif.
The members of a subset of SrtA family sortases are distinguished by their genomic proximity to the gene encoding DNA gyrase subunit A (found in the genera Lactococcus and Streptococcus).

--------Sortase B------------

The second subgroup of enzymes, sortase B, along with its substrate (IsdC in S. aureus), is encoded in an iron transport operon involved in heme-iron uptake.In S. aureus the structural gene for sortase B (srtB) is part of the isd (iron-regulated surface determinant) locus, which is comprised of three transcriptional units, isdA, isdB, and isdCDEF-srtB-isdG.
Enzymes belonging to the sortase B subgroup contain three amino acid segments not found in sortase A and recognize substrates containing an NPQTN motif rather than the canonical LPXTG. The third class, designated sortase C or subfamily 3, contains a C-terminal hydrophobic domain. This group of sortase enzymes is often encoded in multiple copies per genome.
In addition to S. aureus, a single srtB gene is found in bacteria from the genera Bacillus and Listeria, and in all cases, it is proximal to a single substrate that contains an unusual sequence motif (NPQTN in S. aureus; NPKSS in Listeria; and NPKTG, NPKTD, and NPQTG in Bacillus). All SrtB proteins appear to be involved in iron metabolism, since their prospective substrates contain the NEAT domain, implicated in iron transport

--------Subfamily 3 (sortase C)------------
Subfamily 3 enzymes also share a preference for substrates containing the LPXTG cell wall sorting signal motif, often followed by a second G residue. Unlike those for sortase A, the genes for subgroup 3 enzymes are predicted to anchor a much smaller set of substrates, which are typically clustered with the structural gene for the enzyme.

--------Subfamily 4 (sortase D)------------

A fourth subgroup can be defined after alignment of sortase sequences. It has been noted as the sortase D subgroup or subfamilies 4 and 5, as sortases in this subgroup can be distinguished based on the cell wall sorting signals of their associated substrates. Sortases belonging to subfamily 4 are predicted to anchor proteins bearing the unique LPXTA(ST) motif. An alanine residue in the last position of the substrate motif suggests that the subfamily 4 enzymes fulfill a nonredundant role within the cell. These sortases are typically found clustered with their substrates, which usually possess enzymatic function.
----Subfamily 5----------------------------------
Many high-G+C bacteria contain sortases belonging to subfamily 5, and, interestingly, most do not harbor sortase A homologs. This subgroup of sortase enzymes shares substrate specificity for proteins containing an LAXTG motif, and at least in Streptomyces coelicolor they are essential for mycelium and hypha development.

==============REFERENCES:=================================

1. Marraffini LA, Dedent AC, Schneewind O. Sortases and the art of anchoring proteins to the envelopes of gram-positive bacteria. Microbiol Mol Biol Rev. 2006 Mar;70(1):192-221. Review.
PMID: 16524923.

2. Comfort D, Clubb RT.A comparative genome analysis identifies distinct sorting pathways in gram-positive bacteria.Infect Immun. 2004 May;72(5):2710-22.
PMID: 15102780.

3. Mandlik A, Swierczynski A, Das A, Ton-That H.Pili in Gram-positive bacteria: assembly, involvement in colonization and biofilm development.Trends Microbiol. 2008 Jan;16(1):33-40.
PMID: 18083568.