Mycobacterial and Human Nitrobindins: Structure and Function

Aims:Nitrobindins (Nbs) are evolutionary conserved all-beta-barrel heme-proteins displaying a highly solvent-exposed heme-Fe(III) atom. The physiological role(s) of Nbs is almost unknown. Here, the structural and functional properties of ferricMycobacterium tuberculosisNb (Mt-Nb(III)) and ferricHomo sapiensNb (Hs-Nb(III)) have been investigated and compared with those of ferricArabidopsis thalianaNb (At-Nb(III),Rhodnius prolixusnitrophorins (Rp-NP(III)s), and mammalian myoglobins. Results:Data here reported demonstrate thatMt-Nb(III),At-Nb(III), andHs-Nb(III) share withRp-NP(III)s the capability to bind selectively nitric oxide, but display a very low reactivity, if any, toward histamine. Data obtained overexpressingHs-Nb in human embryonic kidney 293 cells indicate thatHs-Nb localizes mainly in the cytoplasm and partially in the nucleus, thanks to a nuclear localization sequence encompassing residues Glu124-Leu154. HumanHs-Nb corresponds to theC-terminal domain of the human nuclear protein THAP4 suggesting that Nb may act as a sensor possibly modulating the THAP4 transcriptional activity residing in theN-terminal region. Finally, we provide strong evidence that bothMt-Nb(III) andHs-Nb(III) are able to scavenge peroxynitrite and to protect freel-tyrosine against peroxynitrite-mediated nitration. Innovation:Data here reported suggest an evolutionarily conserved function of Nbs related to their role as nitric oxide sensors and components of antioxidant systems. Conclusion:Human THAP4 may act as a sensing protein that couples the heme-based Nb(III) reactivity with gene transcription.Mt-Nb(III) seems to be part of the pool of proteins required to scavenge reactive nitrogen and oxygen species produced by the host during the immunity response.