TY - JOUR
T1 - The first histidine triad motif of PhtD is critical for zinc homeostasis in Streptococcus pneumoniae
AU - Eijkelkamp, Bart A.
AU - Pederick, Victoria G.
AU - Plumptre, Charles D.
AU - Harvey, Richard M.
AU - Hughes, Catherine E.
AU - Paton, James C.
AU - McDevitt, Christopher A.
PY - 2016/2
Y1 - 2016/2
N2 - 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 five 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 have not been addressed. We examined the effects of mutating each of the five 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, highlight 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.
AB - 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 five 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 have not been addressed. We examined the effects of mutating each of the five 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, highlight 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.
UR - http://www.scopus.com/inward/record.url?scp=84957676566&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/arc/DP120101432
UR - http://purl.org/au-research/grants/arc/DP120103957
UR - http://purl.org/au-research/grants/arc/DP150101856
UR - http://purl.org/au-research/grants/nhmrc/565526
UR - http://purl.org/au-research/grants/nhmrc/1071659
UR - http://purl.org/au-research/grants/nhmrc/1022240
UR - http://purl.org/au-research/grants/nhmrc/1080784
U2 - 10.1128/IAI.01082-15
DO - 10.1128/IAI.01082-15
M3 - Article
C2 - 26573735
AN - SCOPUS:84957676566
VL - 84
SP - 407
EP - 415
JO - Infection and Immunity
JF - Infection and Immunity
SN - 0019-9567
IS - 2
ER -