Hypoxia-Inducible Factor-1: More Than a Hypoxia-Inducible Transcription Factor

Abstract

In heme-based sensors, a ligand-induced conformational change, initiated at a hemebinding domain, controls the function of a separate transducing domain. For such sensors, there is a considerable range in both the types of heme-binding domains that are possible and the activities to which they can couple. For example, in mammalian soluble guanylyl cyclases (sGC), coupling of a sensory heme-binding domain to a guanylyl cyclase domain permits NO regulation of cGMP, levels (3). A three-dimensional structure is not yet available for the heme-binding domain of sGC, but its sequence suggests that it will not resemble any known heme-protein fold. In the CooA protein of Rhodospirullum rubrum, coupling of a different type of hemebinding domain to a DNA-binding domain allows CO-regulated induction of genes for CO catabolism (4,5). The CooA. protein is unique in that it structurally resembles a catabolite-activator protein (CAP) with heme replacing cAMP. in the regulatory domain (6). So far, O2 signal transduction has offered the greatest variety in the processes controlled, the sensory domains used, and the transducer domains coupled (7). The processes regulated by O2 include nitrogen fixation, cellulose production, and aerotaxis (8-13). At least two types of O2-sensing domains have been identified, one that has a heme-PAS fold and another that is likely to have a myoglobin fold (12,14). The transducing domains are even more varied. They include chemotaxis domains, phosphodiesterase, and histidine-protein kinase domains (2,10,11,15).