SDS22 selectively recognizes and traps metal-deficient inactive PP1

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

doi:10.1073/pnas.1908718116

Title: SDS22 selectively recognizes and traps metal-deficient inactive PP1

Journal Article · 22 September 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1908718116 · OSTI ID:1573470

Choy, Meng S. ^[1]; Moon, Thomas M. ^[1]; Ravindran, Rini ^[2]; Bray, Johnny A. ^[1]; Robinson, Lucy C. ^[2]; Archuleta, Tara L. ^[1]; Shi, Wuxian ^[3]; Peti, Wolfgang ^[1]; Tatchell, Kelly ^[2];

^[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)

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.

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: SC0012704

OSTI ID:: 1573470

Report Number(s):: BNL--212280-2019-JAAM

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 41 Vol. 116; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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