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

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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, MCLP 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.

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Joshua J Filter

Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.
Byron C Williams

Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.
Masumi Eto

Department of Molecular Physiology and Biophysics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
David Shalloway

Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.
Michael L Goldberg

Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States

For correspondence
mlg11@cornell.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0200-0277

Funding

NIH Office of the Director (GM048430)

Michael L Goldberg

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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