Unveiling Molecular Scaffolds of the Type IV Secretion System

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Abstract
In gram-negative bacteria, secretion of macromolecules across the two membranes takes place using diverse macromo- lecular transport assemblies, from simple one-component sys- tems to complex multicomponent machineries. The type IV secretion system (T4SS) is one of the five major secretion systems that are capable of exporting virulence factors across the membranes of gram-negative bacteria. T4SSs are defined as macromolecular transfer systems, the components of which are homologous in sequence and probably in structure to those of conjugative transfer systems of naturally occurring plasmids (35). Several important plant and human pathogens have evolved secretion machineries ancestrally related to conjugation sys- tems for the purpose of delivering virulence effectors (proteins or protein-DNA complexes) to eukaryotic-cell targets. Such pathogens include extracellular organisms such as Agrobacte- rium tumefaciens, the causative agent of crown gall disease, widely used to modify crops genetically; Bordetella pertussis, the agent responsible for whooping cough in children; and Helico- bacter pylori, responsible for gastric ulcers and stomach cancer (3, 6, 9, 52). More recently, intracellular bacterial pathogens, such as Brucella suis, the causative agent of brucellosis, and Legionella pneumoniae, the causative agent of Legionnaires' disease, were shown to require such systems for virulence (5, 32). As more bacterial genomes are being sequenced, the list of putative T4SSs is increasing rapidly, suggesting that macromo- lecular transport by such systems is widespread in nature. This review summarizes recent progress in determining the molecular scaffolds of the structural components of T4SSs. We do not expand on the structural biology of T4SS effectors such as pertussis toxin (44) or the recently determined catalytic core of the relaxase (13).