An induced‐fit conformational change underlies the binding mechanism of the heme‐transport Proteobacteria‐protein HemS

Bacteria rely on their environment and/or host to acquire iron and have evolved specialized systems to sequester and transport heme. The heme‐uptake system HemRSTUV is common to Proteobacteria and a major challenge is to understand the molecular mechanism of heme binding and transfer between the protein molecules that underlie this heme transport, relay process. In the Gram‐negative pathogen Yersinia enterocolitica , the HemRSTUV system culminates with the cytoplasmic recipient HemS which stores and delivers heme for cellular needs. HemS belongs to a family of proteins essential and unique to Proteobacteria. Here we report on the binding mechanism of HemS based on structural data from its apo‐ and ligand‐loaded forms. This heme‐carrier protein associates with its cargo through a novel, partly pre‐formed binding pocket, formed between a large beta‐sheet dome and a three‐helix sub‐domain. Comparison of apo‐ and ligand‐bound HemS crystal structures reveals striking conformational changes that underlie a “heme‐induced fit” binding mechanism. Local shifts in amino acid positions combine with global, rigid body‐like domains movements and together these bring about a switch from an open, apo‐form to a closed, bound‐state. This is the first report in which both liganded and unliganded forms of a heme‐transport protein are described thus providing penetrating insights into its mechanism of heme binding and release.