TY - JOUR
T1 - Picomolar concentrations of free zinc(II) ions regulate receptor protein-tyrosine phosphatase β activity
AU - Wilson, Matthew
AU - Hogstrand, Christer
AU - Maret, Wolfgang
PY - 2012/3/16
Y1 - 2012/3/16
N2 - As key enzymes in the regulation of biological phosphorylations, protein-tyrosine phosphatases are central to the control of cellular signaling and metabolism. Zinc(II) ions are known to inhibit these enzymes, but the physiological significance of this inhibition has remained elusive. Employing metal buffering for strict metal control and performing a kinetic analysis, we now demonstrate that zinc(II) ions are reversible inhibitors of the cytoplasmic catalytic domain of the receptor protein-tyrosine phosphatase beta (also known as vascular endothelial protein-tyrosine phosphatase). The K-t(Zn) value is 21 +/- 7 pM, 6 orders of magnitude lower than zinc inhibition reported previously for this enzyme. It exceeds the affinity of the most potent synthetic small molecule inhibitors targeting these enzymes. Inhibition is in the range of cellular zinc( II) ion concentrations, suggesting that zinc regulates this enzyme, which is involved in vascular physiology and angiogenesis. Thus, for some enzymes that are not recognized as zinc metalloenzymes, zinc binding inhibits rather than activates as in classical zinc enzymes. Activation then requires removal of the inhibitory zinc.
AB - As key enzymes in the regulation of biological phosphorylations, protein-tyrosine phosphatases are central to the control of cellular signaling and metabolism. Zinc(II) ions are known to inhibit these enzymes, but the physiological significance of this inhibition has remained elusive. Employing metal buffering for strict metal control and performing a kinetic analysis, we now demonstrate that zinc(II) ions are reversible inhibitors of the cytoplasmic catalytic domain of the receptor protein-tyrosine phosphatase beta (also known as vascular endothelial protein-tyrosine phosphatase). The K-t(Zn) value is 21 +/- 7 pM, 6 orders of magnitude lower than zinc inhibition reported previously for this enzyme. It exceeds the affinity of the most potent synthetic small molecule inhibitors targeting these enzymes. Inhibition is in the range of cellular zinc( II) ion concentrations, suggesting that zinc regulates this enzyme, which is involved in vascular physiology and angiogenesis. Thus, for some enzymes that are not recognized as zinc metalloenzymes, zinc binding inhibits rather than activates as in classical zinc enzymes. Activation then requires removal of the inhibitory zinc.
U2 - 10.1074/jbc.C111.320796
DO - 10.1074/jbc.C111.320796
M3 - Article
C2 - 22275360
SN - 0021-9258
VL - 287
SP - 9322
EP - 9326
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 12
ER -