Characterization of the Translocation-competent Complex between the Helicobacter pylori Oncogenic Protein CagA and the Accessory Protein CagF

Bonsor, Daniel A.; Weiss, Evelyn; Iosub-Amir, Anat; Reingewertz, Tali H.; Chen, Tiffany; Haas, Rainer; Friedler, Assaf; Fischer, Wolfgang; Sundberg, Eric J.

doi:10.1074/jbc.m113.507657

Cited by 22 publications

(29 citation statements)

References 41 publications

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“…In H. pylori , a positively charged C-terminal tail is important for translocation of the CagA substrate through the Cag T4SS, and this tail can even be exchanged with similar motifs from other effectors to yield CagA translocation [57]. However, CagA translocation additionally requires an intact N-terminal motif of unspecified sequence composition [57] as well as internal motifs required for interaction with the specialized secretion chaperone CagF [58–60]. …”

Section: Substrates/translocation Signals/substrate Docking Reactionsmentioning

confidence: 99%

“…Recently, it was shown that distinct domains of CagF bind to the five domains of CagA, each with μM affinity. The findings led to a proposal that multiple copies of CagF form CagA domain contacts necessary for maintaining the highly labile CagA effector in a translocation-competent, protease-resistant conformation [60]. CagF is also membrane-associated and has been proposed to mediate delivery of CagA to the Cag T4SS [58].…”

Section: Substrates/translocation Signals/substrate Docking Reactionsmentioning

confidence: 99%

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Mechanism and structure of the bacterial type IV secretion systems

Christie¹,

Whitaker²,

González-Rivera³

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

238

209

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The bacterial type IV secretion systems (T4SSs) translocate DNA and protein substrates to bacterial or eukaryotic target cells generally by a mechanism dependent on direct cell-to-cell contact. The T4SSs encompass two large subfamilies, the conjugation systems and the effector translocators. The conjugation systems mediate interbacterial DNA transfer and are responsible for the rapid dissemination of antibiotic resistance genes and virulence determinants in clinical settings. The effector translocators are used by many Gram-negative bacterial pathogens for delivery of potentially hundreds of virulence proteins to eukaryotic cells for modulation of different physiological processes during infection. Recently, there has been considerable progress in defining the structures of T4SS machine subunits and large machine subassemblies. Additionally, the nature of substrate translocation sequences and the contributions of accessory proteins to substrate docking with the translocation channel have been elucidated. A DNA translocation route through the Agrobacterium tumefaciens VirB/VirD4 system was defined, and both intracellular (DNA ligand, ATP energy) and extracellular (phage binding) signals were shown to activate type IV-dependent translocation. Finally, phylogenetic studies have shed light on the evolution and distribution of T4SSs, and complementary structure-function studies of diverse systems have identified adaptations tailored for novel functions in pathogenic settings. This review summarizes the recent progress in our understanding of the architecture and mechanism of action of these fascinating machines, with emphasis on the ‘archetypal’ A. tumefaciens VirB/VirD4 T4SS and related conjugation systems.

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Section: Substrates/translocation Signals/substrate Docking Reactionsmentioning

confidence: 99%

Section: Substrates/translocation Signals/substrate Docking Reactionsmentioning

confidence: 99%

Mechanism and structure of the bacterial type IV secretion systems

Christie¹,

Whitaker²,

González-Rivera³

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

238

209

View full text Add to dashboard Cite

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“…Cagβ is thought to be responsible, probably together with its interaction partner CagZ, for recognition of the CagA T4SS signal sequence [11]. CagF is considered as a CagA secretion chaperone, and recent evidence shows that CagF forms a high-affinity, 1:1 complex with CagA, in which different domains of CagA contribute to binding [36]. …”

Section: Composition Of the Cagt4ssmentioning

confidence: 99%

Composition, Structure and Function of the Helicobacter Pylori cag Pathogenicity Island Encoded type IV Secretion System

2015

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Many Gram-negative pathogens harbor type IV secretion systems (T4SS) that translocate bacterial virulence factors into host cells to hijack cellular processes. The pathology of the gastric pathogen Helicobacter pylori strongly depends on a T4SS encoded by the cag pathogenicity island. This T4SS forms a needle-like pilus, and its assembly is accomplished by multiple protein–protein interactions and various pilus-associated factors that bind to integrins followed by delivery of the CagA oncoprotein into gastric epithelial cells. Recent studies revealed the crystal structures of six T4SS proteins and pilus formation is modulated by iron and zinc availability. All these T4SS interactions are crucial for deregulating host signaling events and disease progression. New developments in T4SS functions and their importance for pathogenesis are discussed.

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“…CagF differs from other T4SS or T3SS secretion chaperones, e.g., A. tumefaciens VirE1. Besides being much larger (32-kDa) than the other (< 5-kDa) chaperones, CagF is highly hydrophobic and recently was shown to bind all five domains of CagA, presumably forming a broad interaction surface that protects the entire protein from degradation (81). CagF binding is also thought to prevent CagA intramolecular interactions of importance for protein function upon translocation to mammalian cells but might block CagA docking with the Cagβ receptor in H. pylori .…”

Section: T4ss Effectors and Their Roles In Pathogenesismentioning

confidence: 99%

“…CagF binding is also thought to prevent CagA intramolecular interactions of importance for protein function upon translocation to mammalian cells but might block CagA docking with the Cagβ receptor in H. pylori . While the nature of the CagA - Cagβ docking reaction remains to be defined, it is evident that the Cag T4SS has appropriated a novel CagF accessory factor to promote stabilization of the large, multidomain CagA substrate and docking with the Cagβ receptor (81). …”

Section: T4ss Effectors and Their Roles In Pathogenesismentioning

confidence: 99%

Mechanism and Function of Type IV Secretion During Infection of the Human Host

2016

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Bacterial pathogens employ type IV secretion systems (T4SSs) for various purposes to aid in survival and proliferation in eukaryotic host. One large T4SS subfamily, the conjugation systems, confers a selective advantage to the invading pathogen in clinical settings through dissemination of antibiotic resistance genes and virulence traits. Besides their intrinsic importance as principle contributors to the emergence of multiply drug-resistant ‘superbugs’, detailed studies of these highly tractable systems have generated important new insights into the mode of action and architectures of paradigmatic T4SSs as a foundation for future efforts aimed at suppressing T4SS machine function. Over the past decade, extensive work on the second large T4SS subfamily, the effector translocators, has identified a myriad of mechanisms employed by pathogens to subvert, subdue, or bypass cellular processes and signaling pathways of the host cell. An overarching theme in the evolution of many effectors is that of molecular mimicry. These effectors carry domains similar to those of eukaryotic proteins and exert their effects through stealthy interdigitation of cellular pathways, often with the outcome not of inducing irreversible cell damage but rather of reversibly modulating cellular functions. This chapter summarizes the major developments for the actively studied pathogens with an emphasis on the structural and functional diversity of the T4SSs and the emerging common themes surrounding effector function in the human host.

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Characterization of the Translocation-competent Complex between the Helicobacter pylori Oncogenic Protein CagA and the Accessory Protein CagF

Cited by 22 publications

References 41 publications

Mechanism and structure of the bacterial type IV secretion systems

Mechanism and structure of the bacterial type IV secretion systems

Composition, Structure and Function of the Helicobacter Pylori cag Pathogenicity Island Encoded type IV Secretion System

Mechanism and Function of Type IV Secretion During Infection of the Human Host

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