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Sallee, N. A. et al. The pathogen protein EspF(U) hijacks actin polymerization using mimicry and multivalency. Nature 454, 1005-1008

Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, USA.
Nature (Impact Factor: 42.35). 07/2008; 454(7207):1005-1008. DOI: 10.1038/nature07170

ABSTRACT Enterohaemorrhagic Escherichia coli attaches to the intestine through actin pedestals that are formed when the bacterium injects its protein EspFU ( also known as TccP) into host cells(1). EspFU potently activates the host WASP ( Wiskott - Aldrich syndrome protein) family of actin- nucleating factors, which are normally activated by the GTPase CDC42, among other signalling molecules. Apart from its amino- terminal type III secretion signal, EspFU consists of five- and- a- half 47- amino- acid repeats. Here we show that a 17- residue motif within this EspFU repeat is sufficient for interaction with N- WASP ( also known as WASL). Unlike most pathogen proteins that interface with the cytoskeletal machinery, this motif does not mimic natural upstream activators: instead of mimicking an activated state of CDC42, EspFU mimics an auto-nhibitory element found within N- WASP. Thus, EspFU activates N- WASP by competitively disrupting the autoinhibited state. By mimicking an internal regulatory element and not the natural activator, EspFU selectively activates only a precise subset of CDC42- activated processes. Although one repeat is able to stimulate actin polymerization, we show that multiple- repeat fragments have notably increased potency. The activities of these EspFU fragments correlate with their ability to coordinate activation of at least two N- WASP proteins. Thus, this pathogen has used a simple autoinhibitory fragment as a component to build a highly effective actin polymerization machine.

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