Sortase Pathways in Gram-Positive Bacteria

Abstract

Research within the past decade has revealed that a large fraction of bacterial surface proteins are covalently anchored to the cell wall by the action of sortase enzymes, in a universally conserved process that is important for infectivity. This chapter presents a review of the structural basis of sortase-mediated cell wall anchoring, drawing on recent structural, biochemical, and bioinformatic studies of this enzyme family. In addition to embedding proteins into the underlying membrane (e.g., membrane proteins and lipoproteins), gram-positive bacteria have developed several methods to display surface proteins, each with its own distinctive structural features. It has long been known that some proteins in gram-positive bacteria are covalently linked to the cell wall, but the enzymes that place them there have only recently been identified. SrtA-related proteins were found in nearly all gram-positive bacteria with sequenced genomes and, in several cases, were demonstrated to be key determinants of infectivity. The broad distribution of sortases in pathogenic bacteria and the essential roles of sortase-anchored surface proteins in the establishment of infection suggest that sortase inhibitors may prove to be effective anti-infective agents. The design of effective sortase inhibitors will require an understanding of the structural biology of sortase-substrate recognition, as well as intimate knowledge of the potentially diverse sortase anchoring pathways and their role in the establishment of infection.