Mycobacterial and Human Nitrobindins: Structure and Function.

Nitrobindins (Nbs) are evolutionary conserved all-β-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 ferric Nb (-Nb(III)) and ferric Nb (-Nb(III)) have been investigated and compared with those of ferric Nb (-Nb(III), nitrophorins (-NP(III)s), and mammalian myoglobins. Data here reported demonstrate that -Nb(III), -Nb(III), and -Nb(III) share with -NP(III)s the capability to bind selectively nitric oxide, but display a very low reactivity, if any, toward histamine. Data obtained overexpressing -Nb in human embryonic kidney 293 cells indicate that -Nb localizes mainly in the cytoplasm and partially in the nucleus, thanks to a nuclear localization sequence encompassing residues Glu124-Leu154. Human -Nb corresponds to the -terminal domain of the human nuclear protein THAP4 suggesting that Nb may act as a sensor possibly modulating the THAP4 transcriptional activity residing in the -terminal region. Finally, we provide strong evidence that both -Nb(III) and -Nb(III) are able to scavenge peroxynitrite and to protect free l-tyrosine against peroxynitrite-mediated nitration. Data here reported suggest an evolutionarily conserved function of Nbs related to their role as nitric oxide sensors and components of antioxidant systems. Human THAP4 may act as a sensing protein that couples the heme-based Nb(III) reactivity with gene transcription. -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.