PAS domains are important signaling modules that monitor changes in light, redox potential, oxygen, small ligands, and overall energy level of a cell. Unlike most other sensor modules, PAS domains are located in the cytosol. There has been a long-standing search for a hypothetical sensor that measures the proton motive force or a similar parameter that reads the energy status inside the cell (18
). The recent discovery of the Aer protein in Escherichia coli
) and progress in functional analysis of the NifL protein in Azotobacter vinelandii
) resulted in a breakthrough in the search for internal energy sensors. These signal-transducing proteins have a PAS domain located inside the cell that senses redox changes in the electron transport system or overall cellular redox status. PAS domains can also sense environmental factors that cross the cell membrane and/or affect cell metabolism.
The advantage for cell survival of sensing oxygen, light, redox potential, and energy levels has been widely recognized. Oxygen is both a terminal acceptor for oxidative phosphorylation with its high ATP yield and a toxic agent that forms harmful reactive free radicals when partially reduced. Many microorganisms are adapted for living within a certain range of oxygen concentrations, as are cells in eukaryotic multicellular organisms. Sensing of light intensity and wavelength governs such cellular responses as phototropism in plants and phototaxis in bacteria. There is increasing evidence that depletion of cellular energy levels is first seen in a decreased electron transport and proton motive force that precede an observable change in ATP concentration. Monitoring electron transport or proton motive force can quickly alert a cell to energy loss. E. coli
senses intracellular redox changes and migrates to a microenvironment with a preferred redox potential (23
). The metabolic effects of oxygen, light, proton motive force, and redox potential are interrelated on the level of the flow of reducing equivalents through the electron transport system. As a result, it is sufficient for individual cells to sense any one of these parameters to monitor cell energy levels. Sensing of oxygen directly may be advantageous in cells that have enzyme reactions that are inactivated by oxygen. Sensing of proton motive force or redox potential may provide a more versatile measure of cellular energy. Recent studies suggest that PAS domains in various sensor proteins vary in the parameter that is sensed. That is, a PAS domain may sense oxygen, light, redox potential, or proton motive force as a way of monitoring energy changes in living cells.
PAS domains have been identified in proteins from all three kingdoms of life: Bacteria, Archaea, and Eucarya. These include histidine and serine/threonine kinases, chemoreceptors and photoreceptors for taxis and tropism, circadian clock proteins, voltage-activated ion channels, cyclic nucleotide phosphodiesterases, and regulators of responses to hypoxia and embryological development of the central nervous system. PAS domains are combined with a variety of regulatory modules in multidomain proteins. As a result, a spectrum of cell responses to changes in the environmental and intracellular conditions are controlled via PAS-containing receptors, transducers, and regulators.
PAS is an acronym formed from the names of the proteins in which imperfect repeat sequences were first recognized: the Drosophila
period clock protein (PER), vertebrate aryl hydrocarbon receptor nuclear translocator (ARNT), and Drosophila
single-minded protein (SIM) (163
). The earliest investigations identified the PAS domain in eukaryotes as a region of approximately 270 amino acid residues that contained two 50-residue conserved sequences termed PAS-A and PAS-B repeats (Fig. A) (40
). Recent studies suggest that a PAS domain comprises a region of approximately 100 to 120 amino acids. PAS-A and PAS-B repeats correspond to the N-terminal half of the respective PAS domains (Fig. B). It is typical to find PAS domains in pairs in eukaryotic transcriptional activators, such as SIM. Microbial proteins contain single, dual, or multiple (up to six) PAS domains.
FIG. 1 Comparison of former (A) and present (B) definitions of PAS domains illustrated with the Drosophila SIM protein. (A) One PAS domain containing two PAS repeats as first described. (B) Two individual PAS domains have been identified in the SIM protein. (more ...)
Several laboratories contributed to the current definition of a PAS domain. Lagarias et al. (131
) identified a motif, similar to a PAS repeat, in an algal phytochrome and in 20 other proteins from both prokaryotes and eukaryotes. They also suggested that this 40-amino-acid motif represents a common fold that might be similar to the N terminus of the photoactive yellow protein, for which the crystallographic structure had been determined (26
). Subsequently, it was recognized that this motif is the most highly conserved block (S1
box) of a larger PAS domain. The motif was extended in the carboxyl direction by defining the S2
box (or PAC motif), and complete PAS domains (including S1
boxes or PAS/PAC motifs) were identified in more than 200 proteins from different organisms throughout the phylogenetic tree (182
). More recently, the entire 125-residue photoactive yellow protein (PYP) (172
), the heme domain of the FixL protein (82
), and the N-terminal domain of the eukaryotic potassium channel HERG (160
) were proposed as structural prototypes for the three-dimensional fold of the PAS domain superfamily. In this review, we present an alignment of the sequences from the PAS domain superfamily that supports this generalization.
The term “PAS domain” is used in this review to denote structures similar to the PYP, FixL, and HERG prototypes or the sequence that constitutes the PAS fold. To refer to regions of sequence similarity, we abandoned the use of S1
) and PAS/PAC (182
) in favor of referring to the PAS structural elements that the sequences specify (172
). The recently described LOV domain (103
) is a PAS domain by our definition, and we do not use the term “LOV.” When consulting the literature on the subject, readers should be aware of the progression in the meaning of “PAS domain.” Further confusion could be avoided by replacing the name “PAS” with a structural designation for the domain.
We have summarized the current knowledge of PAS domains with an emphasis on known and potential sensory and signaling roles in representative prokaryotic and eukaryotic systems. At the time this review was completed (August 1998), the number of identified PAS domains was growing rapidly. We have made no attempt to describe all proteins in which PAS domains are found but hope that our compilation will provide a broader picture of conservation and diversity in signal transduction pathways that involve these unique signaling modules.