Dataset Information

Unfair competition governs the interaction of pCPI-17 with myosin phosphatase (PP1-MYPT1).

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.

SUBMITTER: Filter JJ

PROVIDER: S-EPMC5441869 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Unfair competition governs the interaction of pCPI-17 with myosin phosphatase (PP1-MYPT1).

Filter Joshua J JJ Williams Byron C BC Eto Masumi M Shalloway David D Goldberg Michael L ML

eLife 20170407

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 wh ...[more]

PMID: 28387646

Similar Datasets

Project description:Muscle relaxation is triggered by the dephosphorylation of Ser19 in the myosin regulatory light chain. This reaction is catalyzed by the holoenzyme myosin phosphatase (MP), which includes the catalytic subunit protein phosphatase 1 (PP1) and the regulatory targeting subunit (MYPT). MYPT1 (myosin phosphatase targeting subunit 1) is responsible for both targeting the holoenzyme to subcellular compartments in the muscle and directing PP1 specificity toward myosin. To understand the molecular events leading to the MYPT1-PP1 holoenzyme formation, we used NMR spectroscopy to determine the structural and dynamic characteristics of unbound MYPT1. This allowed the conformations of MYPT1 in the free, unbound state to be directly compared to the PP1-bound state. Our results show that MYPT1(1-98) behaves like a two-domain protein in solution. The first 40 residues of MYPT1(1-98), the disordered region, are intrinsically disordered and highly dynamic, whereas residues 41-98, the folded ankyrin-repeat region, are well-structured and rigid. Furthermore, the integrated use of NMR and biophysical data enabled us to calculate an ensemble model for MYPT1(1-98). The most prominent structural feature of the MYPT1(1-98) ensemble is a 25% populated transient ?-helix in the disordered region of MYPT1(1-98). This ?-helix becomes fully populated when bound to PP1 and, as we show, likely plays a central role in the formation of the MYPT1-PP1 holoenzyme complex. Finally, this combined analysis shows that the structural and dynamic behaviors exhibited by MYPT1 for PP1 are distinct from those of any other previously analyzed PP1 regulatory protein. Collectively, these data enable us to present a new model of the molecular events that drive MYPT1-PP1 holoenzyme formation and demonstrate that there are structural differences in unbound PP1 regulators that have not been previously observed. Thus, this work adds significant insights to the currently limited data for molecular structures and dynamics of PP1 regulators.

Dataset Information

Unfair competition governs the interaction of pCPI-17 with myosin phosphatase (PP1-MYPT1).

Publications

Unfair competition governs the interaction of pCPI-17 with myosin phosphatase (PP1-MYPT1).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets