Breaking the iron piracy code of the TBP system from pathogenic Neisseria.

Abstract

N. gonorrhoeae and N. meningitidis are obligate human pathogens that cause gonorrhea and meningococcal meningitis, respectively. Vaccines are available against N. meningitidis; however, they are not universally effective and there is currently no vaccine against N. gonorrhoeae. And the rapid emergence of drug resistance in these pathogens has elevated their threat to public health, underpinning an immediate need to find better countermeasures. Essential surface machineries are promising therapeutic targets against Neisseria, one of which is called the transferrin-binding protein (Tbp) system consisting of a TonB-dependent transporter called TbpA and a lipoprotein co-receptor TbpB. Together, these proteins mediate iron piracy from human transferrin (hTF). Despite knowing the structures of both receptor proteins for more than a decade, exactly how they coordinate with one another to extract and import the iron from hTF remains unknown. It was hypothesized that iron extraction by TbpA requires energy from the Ton complex present in the inner membrane. In our recent studies though, high-resolution cryo-EM structures of the TbpA+hTF complex and the TbpA+TbpB+hTF complex reveal the Ton complex is not required for iron extraction. Our studies show that TbpA alone is sufficient to extract iron from hTF. To understand the complete mechanism of this iron piracy by the Tbp system, we used time-resolved cryo-EM studies to determine iron bound structures which were supported by EPR studies. Together, our work contributes essential details necessary for deciphering the mechanism Neisseria use for mediating iron piracy during pathogenesis.