The pathogen protein EspF(U) hijacks actin polymerization using mimicry and multivalency.
Enterohaemorrhagic Escherichia coli attaches to the intestine through actin pedestals that are formed when the bacterium injects its protein EspF(U) (also known as TccP) into host cells. EspF(U) 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, EspF(U) consists of five-and-a-half 47-amino-acid repeats. Here we show that a 17-residue motif within this EspF(U) 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, EspF(U) mimics an autoinhibitory element found within N-WASP. Thus, EspF(U) activates N-WASP by competitively disrupting the autoinhibited state. By mimicking an internal regulatory element and not the natural activator, EspF(U) 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 EspF(U) 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.
Sallee
Nathan A
NA
Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, USA.
Rivera
Gonzalo M
GM
Dueber
John E
JE
Vasilescu
Dan
D
Mullins
R Dyche
RD
Mayer
Bruce J
BJ
Lim
Wendell A
WA
D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D054324:Enterohemorrhagic Escherichia coli / Q000378:metabolism* / Q000472:pathogenicity; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D017434:Protein Structure, Tertiary; D012091:Repetitive Sequences, Nucleic Acid; D015398:Signal Transduction / Q000502:physiology; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000737:chemistry / Q000378:metabolism
D000199:Actins; D002352:Carrier Proteins; D029968:Escherichia coli Proteins; C489109:EspFU protein, E coli; D047908:Intracellular Signaling Peptides and Proteins; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal