Abstract
The small phosphoprotein pCPI-17 inhibits myosin light-chain phosphatase (MLCP). Current models postulate that during muscle relaxation, phosphatases other than MLCP dephosphorylate and inactivate pCPI-17 to restore MLCP activity. We show here that such hypotheses are insufficient to account for the observed rapidity of pCPI-17 inactivation in mammalian smooth muscles. Instead, MLCP itself is the critical enzyme for pCPI-17 dephosphorylation. We call the mutual sequestration mechanism through which pCPI-17 and MLCP interact inhibition by unfair competition: MLCP protects pCPI-17 from other phosphatases, while pCPI-17 blocks other substrates from MLCP's active site. MLCP dephosphorylates pCPI-17 at a slow rate that is, nonetheless, both sufficient and necessary to explain the speed of pCPI-17 dephosphorylation and the consequent MLCP activation during muscle relaxation.
Highlights
The phosphorylation of certain small proteins converts these polypeptides into inhibitors of PPP family phosphatases [reviewed by (Eto and Brautigan, 2012)]
Consistent with the known activities of myosin light-chain phosphatase (MLCP), we found that the complex we purified is able to dephosphorylate the myosin regulatory light chain; the C terminal domain of ERM proteins, which are physiological MLCP substrates (Eto et al, 2005, 2000; Fukata et al, 1998)]; and the nonspecific substrate myelin basic protein
Previous studies concluded that the dephosphorylation of pCPI-17 is accomplished by phosphatases other than MLCP [other PP1 holoenzymes, PP2A, and PP2C (Eto and Brautigan, 2012; Eto et al, 2004; Hersch et al, 2004; Kitazawa, 2010; Obara et al, 2010; Takizawa et al, 2002)] that can react with pCPI-17 much faster than MLCP
Summary
The phosphorylation of certain small proteins converts these polypeptides into inhibitors of PPP family phosphatases [reviewed by (Eto and Brautigan, 2012)]. These phosphoproteins have extremely strong affinities for the holoenzymes they target with IC50 values in the nanomolar/ subnanomolar range. Either the enzyme cannot dephosphorylate the pseudosubstrate, or the dephosphorylation is too slow to contribute meaningfully to the system’s reboot In these models, the inhibition can only be relieved by dissociation of the phosphorylated inhibitor from the enzyme and its subsequent dephosphorylation by other phosphatases. The inhibited enzyme itself must dephosphorylate the inhibitor at a carefully calibrated rate that is slow enough to maintain inhibition but fast enough to permit speedy physiological responses
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