Abstract Heme-based sensor proteins are pivotal regulatory biomolecules that utilize the iron-protoporphyrin IX complex to detect environmental cues. This review examines the structural diversity and signaling mechanisms of these sensors, categorized by their primary ligands. I discuss CO sensors like CooA, RcoM, and NPAS2; O2 sensors including FixL, EcDosP, HemAT, Aer2, and DpHemDGC; and NO sensors such as sGC and H-NOX domains. The signaling process begins with ligand binding at the heme iron, triggering conformational changes, often involving PAS, GAF, or globin-like domains, that are propagated allosterically to distal effector domains. Beyond its role as a stable prosthetic group, I also explore the emerging paradigm of heme as a signaling molecule, where “labile heme” directly modulates targets like ion channels and transcription factors. By synthesizing recent structural insights, this review elucidates how these molecular switches translate chemical inputs into biological outputs. Understanding these sophisticated systems offers significant potential for synthetic biology and the development of therapeutics targeting gas-signaling pathways.
Shigetoshi Aono (Wed,) studied this question.