MptpB, a virulence factor from Mycobacterium tuberculosis, exhibits triple-specificity phosphatase activity.
Bacterial pathogens have developed sophisticated mechanisms of evading the immune system to survive in infected host cells. Central to the pathogenesis of Mycobacterium tuberculosis is the arrest of phagosome maturation, partly through interference with PtdIns signalling. The protein phosphatase MptpB is an essential secreted virulence factor in M. tuberculosis. A combination of bioinformatics analysis, enzyme kinetics and substrate-specificity characterization revealed that MptpB exhibits both dual-specificity protein phosphatase activity and, importantly, phosphoinositide phosphatase activity. Mutagenesis of conserved residues in the active site signature indicates a cysteine-based mechanism of dephosphorylation and identifies two new catalytic residues, Asp165, essential in catalysis, and Lys164, apparently involved in substrate specificity. Sequence similarities with mammalian lipid phosphatases and a preference for phosphoinositide substrates suggests a potential novel role of MptpB in PtdIns metabolism in the host and reveals new perspectives for the role of this phosphatase in mycobacteria pathogenicity.
Beresford
Nicola
N
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester M13 9PT, UK.
Patel
Sumayya
S
Armstrong
Jane
J
Szöor
Balázs
B
Fordham-Skelton
Anthony P
AP
Tabernero
Lydia
L
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D005658:Fungi / Q000201:enzymology; D007700:Kinetics; D050356:Lipid Metabolism; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000472:pathogenicity*; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D037521:Virulence Factors / Q000737:chemistry / Q000378:metabolism*
D001426:Bacterial Proteins; C414465:MptpA protein, Mycobacterium tuberculosis; D010716:Phosphatidylinositols; D037521:Virulence Factors; D017027:Protein Tyrosine Phosphatases