Crystal Structure and Metal Binding Properties of the Lipoprotein MtsA, Responsible for Iron Transport in Streptococcus pyogenes

An ability to acquire iron is essential for the viability and growth of almost all organisms and in pathogenic bacteria is strongly correlated with virulence. The cell surface lipoprotein MtsA, a component of the MtsABC transporter of Streptococcus pyogenes, acts as the primary receptor for inorganic iron by this significant human pathogen. Iron is bound as Fe2+, with the participation of bicarbonate. The crystal structure of MtsA has been determined and refined at 1.8 angstrom resolution (R = 0. 167, and R-free = 0.194). MtsA has the classic bacterial metal binding receptor (MBR) fold, with the Fe2+ ion bound to the side chains of His68, His140, Glu206, and Asp281, at a totally enclosed site between the two domains of the protein. The absence of bicarbonate from the binding site suggests that it is displaced during the final stages of metal binding. Both the fold and metal binding site are most similar to those of the manganese receptors PsaA and MntC, consistent with the similar coordination requirements of Fe2+ and Mn2+. Binding studies confirm a 10-fold preference for Fe2+ over Mn2+ although both may be carried in vivo. Mutational analysis of the binding site shows that His140 is critical for a fully functional binding site but that Glu206 is dispensable. The crystal structure explains the distinct roles of these ligands and also reveals potential secondary binding sites that may explain the binding behavior of MtsA for metal ions other than Fe2+.