Sortase enzymes in Gram‐positive bacteria

Abstract

SummaryIn Gram-positive bacteria proteins are displayed on the cell surface using sortase enzymes. These cysteine transpeptidases join proteins bearing an appropriate sorting signal to strategically positioned amino groups on the cell surface. Working alone, or in concert with other enzymes, sortases either attach proteins to the cross-bridge peptide of the cell wall or they link proteins together to form pili. Because surface proteins play a fundamental role in microbial physiology and are frequently virulence factors, sortase enzymes have been intensely studied since their discovery a little more than a decade ago. Based on their primary sequences and functions sortases can be partitioned into distinct families called class A to F enzymes. Most bacteria elaborate their surfaces using more than one type of sortase that function non-redundantly by recognizing unique sorting signals within their protein substrates. Here we review what is known about the functions of these enzymes and the molecular basis of catalysis. Particular emphasis is placed on 'pilin' specific class C sortases that construct structurally complex pili. Exciting new data have revealed that these enzymes are amazingly promiscuous in the substrates that they can employ and that there is a startling degree of diversity in their mechanism of action. We also review recent data that suggest that sortases are targeted to specific sites on the cell surface where they work with other sortases and accessory factors to properly function.

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

“…Sortases and surface proteins with LPXTG sorting signals are found in other nosocomial pathogens, for example, Enterococcus faecalis, Enterococcus faecium, and Clostridium difficile (66)(67)(68). Earlier work revealed the contribution of sortase toward enterococcal virulence and the pathogenesis of urinary tract infections or endocarditis (67,69,70).…”

Structure of the Bacillus anthracis Sortase A Enzyme Bound to Its Sorting Signal

“…Sortase enzymes are used by Gram-positive bacteria to covalently attach protein virulence factors to the bacterial cell surface and therefore are promising drug targets (6,67). An understanding of the mechanism of substrate recognition could facilitate the rational development of sortase inhibitors.…”

“…4A) B. anthracis (strain AHG188) that was transformed with plasmid (pAHG322) that expresses wild-type or mutated Ba SrtA, as well as the BasC FLAG/MH6 reporter protein. BasC FLAG/MH6 has previously been shown to be anchored to the cell wall by sortase and contains the full-length BasC substrate of sortase harboring an active cell wall sorting signal, as well as His 6 and FLAG tags that facilitate its fractionation and immunoblot detection, respectively (20). The cell wall of B. anthracis was fractionated and BasC FLAG/MH6 was detected by immunoblotting with anti-FLAG polyclonal antibodies.…”

“…Based on their primary sequences members of the sortase superfamily can be partitioned into at least six subfamilies, called class A to F enzymes (6,17,18). The genome of B. anthracis encodes class A, B, and D sortases, known as Ba SrtA, Ba SrtB, and Ba SrtC, respectively (19).…”

Sortase-deficient lactobacilli: effect on immunomodulation and gut retention

“…The sortase enzyme then cleaves between the Thr and Gly residues, at which point the sortase and SDP form a complex linked by a thioester acyl bond. This bond is then subjected to nucleophilic attack; the SDP is subsequently linked to lipid II, and incorporated as part of the cell wall biosynthetic process (Hendrickx et al, 2011;Kleerebezem et al, 2010;Maresso & Schneewind, 2008;Spirig et al, 2011).…”