期刊
NATURE
卷 469, 期 7328, 页码 107-U127出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature09593
关键词
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资金
- US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- NIH [5T32AI007520-12]
- Welch Foundation [I-1704]
- NIH (NIAID) [1RO1AI083359-01]
The fidelity and specificity of information flow within a cell is controlled by scaffolding proteins that assemble and link enzymes into signalling circuits(1,2). These circuits can be inhibited by bacterial effector proteins that post-translationally modify individual pathway components(3-6). However, there is emerging evidence that pathogens directly organize higher-order signalling networks through enzyme scaffolding(7,8), and the identity of the effectors and their mechanisms of action are poorly understood. Here we identify the enterohaemorrhagic Escherichia coli O157:H7 type III effector EspG as a regulator of endomembrane trafficking using a functional screen, and report ADP-ribosylation factor (ARF) GTPases and p21-activated kinases (PAKs) as its relevant host substrates. The 2.5 angstrom crystal structure of EspG in complex with ARF6 shows how EspG blocks GTPase-activating-protein-assisted GTP hydrolysis, revealing a potent mechanism of GTPase signalling inhibition at organelle membranes. In addition, the 2.8 angstrom crystal structure of EspG in complex with the autoinhibitory I alpha 3-helix of PAK2 defines a previously unknown catalytic site in EspG and provides an allosteric mechanism of kinase activation by a bacterial effector. Unexpectedly, ARF and PAKs are organized on adjacent surfaces of EspG, indicating its role as a 'catalytic scaffold' that effectively reprograms cellular events through the functional assembly of GTPase-kinase signalling complex.
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