Abstract
Author SummaryA central question in biological signal transduction is how cell-surface receptors transmit signals from the outside world across cell membranes and into the cells themselves. In bacteria and lower eukaryotes such receptors are composed of individual modules responsible for specific functions (e.g., sensing, relay, or output). HAMP domains act as the signal relay modules in many receptors, physically bridging input and output components and transferring signals between them. Through a combination of crystallographic, biophysical, spectroscopic, and functional studies we are able to associate two structurally defined HAMP conformational states with functional “on” and “off” signals in bacterial chemoreceptors, and thereby resolve the mechanism by which HAMPs can relay information. The two states differ in both their structure and dynamics and appear to enforce their properties on downstream output modules. Chemoreceptors allow bacteria to track chemical gradients with exquisite sensitivity and dynamic range; we further show that the response to chemoattractant depends critically on specific HAMP residues close to the membrane. Finally, based on the switching mechanism, we design and generate an inverse signaling HAMP domain that provides a new tool to engineer bacterial responses and may be especially advantageous in remediation efforts for directing bacteria towards chemicals that are normally repellants.
Highlights
The ability of single-celled organisms to sense, respond to, and adapt to their changing environment requires receptor proteins to convert extracellular signals into cellular responses [1]
HAMP domains act as the signal relay modules in many receptors, physically bridging input and output components and transferring signals between them
Chemoreceptors allow bacteria to track chemical gradients with exquisite sensitivity and dynamic range; we further show that the response to chemoattractant depends critically on specific HAMP residues close to the membrane
Summary
The ability of single-celled organisms to sense, respond to, and adapt to their changing environment requires receptor proteins to convert extracellular signals into cellular responses [1]. Central to many of these signal transduction systems are HAMP domains, which act to couple sensory and output domains in over 26,000 different receptor proteins [2]. HAMP domains connect to transmembrane helices entering the cytoplasm and translate chemical, photo, and thermo stimuli to the output of cytoplasmic catalytic domains (mainly histidine kinases, adenylyl cyclases, methyl-accepting chemotaxis proteins [MCPs], and phosphatases) [3]. A spectrum of HAMP domain structures and conformations is characterized for native and mutant HAMP domains, the most divergent of which differ by helix rotation, helix translation, and helix–helix crossing angle [5,7,8,9,10,11]. The transmembrane helices of characterized HAMP-containing receptors are known to undergo small amplitude translations or rotations during signal transduction [12,13]
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