Infect Immun. 2015 Nov 16. pii: IAI.01082-15. [Epub ahead of print]

The first histidine triad motif of PhtD is critical for zinc homeostasis in Streptococcus pneumoniae.

Eijkelkamp BA1, Pederick VG1, Plumptre CD1, Harvey RM1, Hughes CE1, Paton JC1, McDevitt CA2.

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Streptococcus pneumoniae is the world's foremost human pathogen. Acquisition of the first row transition metal ion zinc is essential for pneumococcal colonization and disease. Zinc is acquired via the ATP-binding cassette transporter AdcCB, and two zinc-binding proteins, AdcA and AdcAII. We have previously shown that AdcAII is reliant upon the polyhistidine triad (Pht) proteins to aid in zinc recruitment. Pht proteins generally contain 5 histidine (His) triad motifs that are believed to facilitate zinc binding and, therefore, play a significant role in pneumococcal metal ion homeostasis. However, the importance and potential redundancy of these motifs has not been addressed. Here, we examine the effects of mutating each of the 5 His triad motifs of PhtD. The combination of in vitro growth assays, active zinc uptake and PhtD expression studies, show that the His triad closest to the protein's amino-terminus is the most important for zinc acquisition. Intriguingly, in vivo competitive infection studies investigating the amino- and carboxyl-terminal His-triad mutants indicate that the motifs have similar importance in colonization. Collectively, our new insights into the contributions of the individual His triad motifs of PhtD, and by extension the other Pht proteins, highlights the crucial role of the first His triad site in zinc acquisition. This study also suggests that the Pht proteins likely play a role beyond zinc acquisition in pneumococcal virulence.

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PMID: 26573735 [PubMed - as supplied by publisher]