SDS22 selectively recognizes and traps metal-deficient inactive PP1
Abstract
The metalloenzyme protein phosphatase 1 (PP1), which is responsible for ≥50% of all dephosphorylation reactions, is regulated by scores of regulatory proteins, including the highly conserved SDS22 protein. SDS22 has numerous diverse functions, surprisingly acting as both a PP1 inhibitor and as an activator. Here, we integrate cellular, biophysical, and crystallographic studies to address this conundrum. We discovered that SDS22 selectively binds a unique conformation of PP1 that contains a single metal (M2) at its active site, i.e., SDS22 traps metal-deficient inactive PP1. Furthermore, we showed that SDS22 dissociation is accompanied by a second metal (M1) being loaded into PP1, as free metal cannot dissociate the complex and M1-deficient mutants remain constitutively trapped by SDS22. Together, our findings reveal that M1 metal loading and loss are essential for PP1 regulation in cells, which has broad implications for PP1 maturation, activity, and holoenzyme subunit exchange.
- Authors:
-
[1]
- Univ. of Arizona, Tucson, AZ (United States)
- Louisiana State Univ. Health Sciences Center, Shreveport, LA (United States)
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Publication Date:
- Research Org.:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1573470
- Report Number(s):
- BNL-212280-2019-JAAM
Journal ID: ISSN 0027-8424
- Grant/Contract Number:
- SC0012704
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 116; Journal Issue: 41; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Choy, Meng S., Moon, Thomas M., Ravindran, Rini, Bray, Johnny A., Robinson, Lucy C., Archuleta, Tara L., Shi, Wuxian, Peti, Wolfgang, Tatchell, Kelly, and Page, Rebecca. SDS22 selectively recognizes and traps metal-deficient inactive PP1. United States: N. p., 2019.
Web. doi:10.1073/pnas.1908718116.
Choy, Meng S., Moon, Thomas M., Ravindran, Rini, Bray, Johnny A., Robinson, Lucy C., Archuleta, Tara L., Shi, Wuxian, Peti, Wolfgang, Tatchell, Kelly, & Page, Rebecca. SDS22 selectively recognizes and traps metal-deficient inactive PP1. United States. https://doi.org/10.1073/pnas.1908718116
Choy, Meng S., Moon, Thomas M., Ravindran, Rini, Bray, Johnny A., Robinson, Lucy C., Archuleta, Tara L., Shi, Wuxian, Peti, Wolfgang, Tatchell, Kelly, and Page, Rebecca. Mon .
"SDS22 selectively recognizes and traps metal-deficient inactive PP1". United States. https://doi.org/10.1073/pnas.1908718116. https://www.osti.gov/servlets/purl/1573470.
@article{osti_1573470,
title = {SDS22 selectively recognizes and traps metal-deficient inactive PP1},
author = {Choy, Meng S. and Moon, Thomas M. and Ravindran, Rini and Bray, Johnny A. and Robinson, Lucy C. and Archuleta, Tara L. and Shi, Wuxian and Peti, Wolfgang and Tatchell, Kelly and Page, Rebecca},
abstractNote = {The metalloenzyme protein phosphatase 1 (PP1), which is responsible for ≥50% of all dephosphorylation reactions, is regulated by scores of regulatory proteins, including the highly conserved SDS22 protein. SDS22 has numerous diverse functions, surprisingly acting as both a PP1 inhibitor and as an activator. Here, we integrate cellular, biophysical, and crystallographic studies to address this conundrum. We discovered that SDS22 selectively binds a unique conformation of PP1 that contains a single metal (M2) at its active site, i.e., SDS22 traps metal-deficient inactive PP1. Furthermore, we showed that SDS22 dissociation is accompanied by a second metal (M1) being loaded into PP1, as free metal cannot dissociate the complex and M1-deficient mutants remain constitutively trapped by SDS22. Together, our findings reveal that M1 metal loading and loss are essential for PP1 regulation in cells, which has broad implications for PP1 maturation, activity, and holoenzyme subunit exchange.},
doi = {10.1073/pnas.1908718116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 41,
volume = 116,
place = {United States},
year = {Mon Sep 23 00:00:00 EDT 2019},
month = {Mon Sep 23 00:00:00 EDT 2019}
}
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