4.6 Article

Hydrogen exchange of chemoreceptors in functional complexes suggests protein stabilization mediates long-range allosteric coupling

期刊

JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 44, 页码 16062-16079

出版社

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.009865

关键词

allosteric regulation; bacterial signal transduction; chemotaxis; hydrogen-deuterium exchange; intrinsically disordered protein; membrane protein; protein complex; receptor structure-function; chemoreceptor; transmembrane signaling

资金

  1. National Institutes of Health [R01-GM085288, R01-GM120195]

向作者/读者索取更多资源

Bacterial chemotaxis receptors form extended hexagonal arrays that integrate and amplify signals to control swimming behavior. Transmembrane signaling begins with a 2-? ligand-induced displacement of an ? helix in the periplasmic and transmembrane domains, but it is unknown how the cytoplasmic domain propagates the signal an additional 200 ? to control the kinase CheA bound to the membrane-distal tip of the receptor. The receptor cytoplasmic domain has previously been shown to be highly dynamic as both a cytoplasmic fragment (CF) and within the intact chemoreceptor; modulation of its dynamics is thought to play a key role in signal propagation. This hydrogen deuterium exchange-MS (HDX-MS) study of functional complexes of CF, CheA, and CheW bound to vesicles in native-like arrays reveals that the CF is well-ordered only in its protein interaction region where it binds CheA and CheW. We observe rapid exchange throughout the rest of the CF, with both uncorrelated (EX2) and correlated (EX1) exchange patterns, suggesting the receptor cytoplasmic domain retains disorder even within functional complexes. HDX rates are increased by inputs that favor the kinase-off state. We propose that chemoreceptors achieve long-range allosteric control of the kinase through a coupled equilibrium: CheA binding in a kinase-on conformation stabilizes the cytoplasmic domain, and signaling inputs that destabilize this domain (ligand binding and demethylation) disfavor CheA binding such that it loses key contacts and reverts to a kinase-off state. This study reveals the mechanistic role of an intrinsically disordered region of a transmembrane receptor in long-range allostery.

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