The Role of Quaternary Structure in the Signaling Mechanisms of PAS Sensor Domains

Abstract

The modular nature of proteins containing PAS (Per-ARNT-Sim) or other sensor domains enables signaling networks to be diverse and poses an interesting question: how can sensor domains with largely conserved tertiary structures regulate effector domains with very diverse structures and functions? We address this question by examining signal processing by the PAS sensor domain, which can regulate the activity of covalently linked effector domains such as a kinase, phosphodiesterase or DNA binding domains. In many cases oligomerization of sensor proteins is essential for signal transduction. We present the structure of a heme-PAS domain dimer from Bradyrhizobium japonicum (bjFixLH) in a new space group (P1) and at higher resolutions (1.5-1.8 A) than those previously obtained. Interestingly, bjFixLH can form two different dimers in the same crystallization solution, where the monomers in one dimer are rotated ∼175° relative to the second. This suggests that PAS monomers are plastic and that two quite distinct quaternary structures are closely similar in free energy. Comparison of PAS domain dimers using screw rotation analysis reveals that PAS monomers adopt a discrete range of monomer orientations. Similar to the light-sensitive PAS domain YtvA-LOV from Bacillus subtilis, bjFixLH undergoes signal-induced quaternary structural changes where monomers rotate ∼2° relative to each other. Signal-induced quaternary structural changes accommodate the ability of PAS sensor domains to regulate a wide variety of effector domains since PAS and effector domains would not be required to interact with each other in a structure-specific manner. Our results will guide the rational design of novel PAS signaling proteins.