Pneumococcal histidine triads – involved not only in Zn²⁺, but also Ni²⁺ binding?

Polyhistidine triad proteins, which participate in Zn²⁺ uptake in Streptococcus pneumoniae, contain multiple copies of the HxxHxH (histidine triad motif) sequence. We focus on three such motifs from one of the most common and well-conserved polyhistidine triad proteins, PhtA, in order to understand their bioinorganic chemistry; particular focus is given to (i) understanding which of the PhtA triads binds Zn²⁺ with the highest affinity (and why) and (ii) explaining whether Ni²⁺ (also crucial for bacterial survival and virulence) could potentially outcompete Zn²⁺ at its native binding site. There is no significant difference in the stability of zinc(II) complexes with the three studied protein fragments, but one of the nickel(II)–polyhistidine triads is remarkably stable; we explain why and hypothesize about the biological importance of this finding.