Crystal structure of hemopexin reveals a novel high-affinity heme site formed between two beta-propeller domains

The ubiquitous use of heme in animals poses severe biological and chemical challenges. Free heme is toxic to cells and is a potential source of iron f or pathogens. For protection, especially in conditions of trauma, inflammat ion and hemolysis, and to maintain iron homeostasis, a high-affinity bindin g protein, hemopexin, is required. Hemopexin binds heme with the highest af finity of any known protein, but releases it into cells via specific recept ors. The crystal structure of the heme-hemopexin complex reveals a novel he me binding site, formed between two similar four-bladed P-propeller domains and bounded by the interdomain linker. The ligand is bound to two histidin e residues in a pocket dominated by aromatic and basic groups. Further stab ilization is achieved by the association of the two P-propeller domains, wh ich form on extensive polar interface that includes a cushion of ordered wa ter molecules. We propose mechanisms by which these structural features pro vide the dual function of heme binding and release.