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    Functional Elements of EspF<sub>u</sub>, an Enterohemorrhagic <em>E. coli</em> Effector that Stimulates Actin Assembly: A Dissertation

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    Authors
    Skehan, Brian M.
    Faculty Advisor
    John M. Leong
    Academic Program
    MD/PhD
    UMass Chan Affiliations
    Molecular Genetics and Microbiology
    Document Type
    Doctoral Dissertation
    Publication Date
    2009-06-17
    Keywords
    Enterohemorrhagic Escherichia coli
    Escherichia coli Proteins
    Microfilament Proteins
    Actins
    Carrier Proteins
    Receptors
    Cell Surface
    Amino Acids, Peptides, and Proteins
    Bacteria
    Macromolecular Substances
    
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    Abstract
    Enterohemorrhagic Escherichia coli O157:H7 (EHEC) is an attaching and effacing pathogen that upon attachment to host cells, induce characteristic attaching and effacing lesions and formation of F-actin rich pedestals beneath sites of bacterial attachment. EHEC harbors a Type III secretion system through which it delivers dozens of effectors into the host cell. The two secreted effectors critical for EHEC-mediated actin pedestal formation are the translocated intimin receptor (Tir) and EspFU. EspFU consists of an N-terminal secretion signal and a C-terminus containing six tandem 47-residue proline-rich repeats, each of which can bind and activate the actin nucleation promoting factor N-WASP. Structural and functional analyses described here have identified the mechanism of N-WASP activation by EspFU and the minimal domains and specific residues required for this activity. While EspFU and Tir are the only bacterial effectors required for F-actin pedestal formation, recruitment of EspFU to Tir is mediated by an unidentified putative host factor. To identify the host factor responsible for linking these two effectors, a combination of in vitro and functional assays were used to identify the host factor, IRTKS and the residues required for these interactions were defined. Further, the presence of at least two 47-residue repeats in all characterized clinical isolates of canonical EHEC strains led us to address the minimal requirements for EspFU functional domains to promote recruitment to Tir and N-WASP activation. Here we show that two proline-rich elements of EspFU are required for recruitment of EspFU by IRTKS to sites of bacterial attachment. Furthermore, once artificially clustered at the membrane, a single N-WASP binding element of EspFU can induce actin pedestal formation.
    DOI
    10.13028/y7mt-8035
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31772
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/y7mt-8035
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