Bacteria have a tough life. They must find clever ways to outwit the cruel environment in order to survive. To do this, they use sophisticated signaling systems that tell them where they are, and help them swim to better places. These systems are great models for more complicated sensory systems in higher organisms because bacteria are easy to study.
Escherichia coli has five receptors that sense nutrients and monitor oxygen concentration. These chemosensors co-ordinate multiple environmental signals and tell the bacteria which way to swim. Four of the receptors (Tsr, Tar, Trg, and Tap) are chemotaxis proteins that bind specific ligands and transmit information across the cell membrane. The fifth receptor, Aer, is a cytosolic sensor of aerotaxis, energy, and redox.
The Aer protein contains an N-terminal PAS domain and C-terminal HAMP and signaling domains. These regions flank an intervening hydrophobic segment that anchors Aer to the cytosolic membrane. The Aer PAS domain is a member of the PAS super-family, whose various members sense light, oxygen, redox potential, energy, and voltage; bind small ligands, and participate in protein-protein interactions. Although the sequence identity of the PAS super-family is low, their three-dimensional structures are highly conserved, suggesting a common mechanism may be used for signaling by different PAS domains. The overall architecture of a PAS domain has been described as a left-handed glove that can enclose a cofactor (FAD in the case of Aer). Cofactor sensing presumably involves a change in the state of the cofactor that alters local interactions in the binding cleft of the PAS domain. These changes are then transmitted to, and amplified in, other regions of the protein. In the case of Aer, we believe that the PAS domain transmits conformational signals to the C-terminal HAMP domain.
HAMP domains are important signal transduction modules found in a large number of sensory proteins. They frequently link signal input and output domains, and as such, HAMP domains are important transmitters of sensory information. The mechanism by which HAMP domains perform this task is unknown and is therefore the subject of current research in the laboratory. The mechanism used by HAMP domains to transform and transmit sensory information will likely apply to many different proteins in diverse biological systems.
Based on amino acid sequence, HAMP domains are predicted to contain two amphipathic helices (named AS-1 and AS-2) connected by a loop. This organization was recently supported by the first reported structure of a HAMP domain (1). In the NMR structure of the protein from the archaeon A. fulgidus, the AS-1 and AS-2 segments formed a parallel, four-stranded coiled coil bundle. The figure on this page shows a model of an Aer-HAMP dimer, created using the co-ordinates of the A. fulgidus Afl503 HAMP domain, but using the sequence of Aer. Since we believe that the Aer-HAMP domain interacts with Aer-PAS, a domain not present in the Afl503 protein, the structure of the Aer-HAMP domain may, or may not, be similar to the Afl503-HAMP domain. In recent studies, we probed the structure of the Aer-HAMP region by disulfide crosslinking and made comparisons with the resolved structure of the archaeal HAMP domain. As shown in the figure, the major crosslinkers in AS-1 and AS-2 occurred at the dimer interface between cognate AS-1 and AS-2 helices. The Aer-HAMP domain is therefore likely to form a four-helix bundle similar to that formed by the A. fulgidus HAMP domain. However, many interesting questions still need to be answered, such as 1) what are the specific interactions between AS-1 and AS-2?, 2) how are these specific interactions translated into a signal?, and 3) how does the PAS domain regulate signaling by the HAMP domain? Questions such as these form the basis of our current research efforts.
1. Hulko M, Berndt F, Gruber M, Linder JU, Truffault V, Schultz A, Martin J, Schultz JE, Lupas AN, and Coles M. 2006. The HAMP domain structure implies helix rotation in transmembrane signaling. Cell 126:929-40.
Watts KJ, Sommer K, Fry SL, Johnson MS, and Taylor BL. 2006. Function of the N-terminal cap of the PAS domain in signaling by the aerotaxis receptor Aer. J Bacteriol. 188(6):2154-62. Erratum in: J Bacteriol. 188(9):3429.
Watts KJ, Johnson MS, and Taylor BL. 2006. Minimal requirements for oxygen sensing by the aerotaxis receptor Aer. Mol Microbiol. 59(4):1317-26.
Watts KJ, Ma Q, Johnson MS, and Taylor BL. 2004. Interactions between the PAS and HAMP domains of the Escherichia coli aerotaxis receptor Aer. J Bacteriol. 186(21):7440-49.
Yu HS, Saw JH, Hou S, Larsen RW, Watts KJ, Johnson MS, Zimmer MA, Ordal GW, Taylor BL, and Alam M. 2002. Aerotactic responses in bacteria to photoreleased oxygen. FEMS Microbiol Lett. 217(2):237-42.
Watts KJ, Thompson CH, Cossart YE, and Rose BR. 2002. Sequence variation and physical state of human papillomavirus type 16 cervical cancer isolates from Australia and New Caledonia. Int J Cancer. 97(6):868-74.
Watts KJ, Thompson CH, Cossart YE, and Rose BR. 2001. Variable oncogene promoter activity of human papillomavirus type 16 cervical cancer isolates from Australia. J Clin Microbiology. 39(5):2009-14.
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Last Revised: Tue, Dec 19, 2006