Structure-Function Analysis of PPP1R3D, a Protein Phosphatase 1 Targeting Subunit, Reveals a Binding Motif for 14-3-3 Proteins which Regulates its Glycogenic Properties

PLoS One. 2015 Jun 26;10(6):e0131476. doi: 10.1371/journal.pone.0131476. eCollection 2015.

Abstract

Protein phosphatase 1 (PP1) is one of the major protein phosphatases in eukaryotic cells. It plays a key role in regulating glycogen synthesis, by dephosphorylating crucial enzymes involved in glycogen homeostasis such as glycogen synthase (GS) and glycogen phosphorylase (GP). To play this role, PP1 binds to specific glycogen targeting subunits that, on one hand recognize the substrates to be dephosphorylated and on the other hand recruit PP1 to glycogen particles. In this work we have analyzed the functionality of the different protein binding domains of one of these glycogen targeting subunits, namely PPP1R3D (R6) and studied how binding properties of different domains affect its glycogenic properties. We have found that the PP1 binding domain of R6 comprises a conserved RVXF motif (R102VRF) located at the N-terminus of the protein. We have also identified a region located at the C-terminus of R6 (W267DNND) that is involved in binding to the PP1 glycogenic substrates. Our results indicate that although binding to PP1 and glycogenic substrates are independent processes, impairment of any of them results in lack of glycogenic activity of R6. In addition, we have characterized a novel site of regulation in R6 that is involved in binding to 14-3-3 proteins (RARS74LP). We present evidence indicating that when binding of R6 to 14-3-3 proteins is prevented, R6 displays hyper-glycogenic activity although is rapidly degraded by the lysosomal pathway. These results define binding to 14-3-3 proteins as an additional pathway in the control of the glycogenic properties of R6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism*
  • Amino Acid Sequence
  • Animals
  • Binding Sites / genetics
  • Glycogen / metabolism*
  • Glycogenolysis / genetics
  • HEK293 Cells
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Interaction Domains and Motifs* / genetics
  • Protein Phosphatase 1 / chemistry
  • Protein Phosphatase 1 / genetics
  • Protein Phosphatase 1 / metabolism*
  • Protein Subunits
  • Structure-Activity Relationship

Substances

  • 14-3-3 Proteins
  • Protein Subunits
  • Glycogen
  • PPP1R3D protein, human
  • Protein Phosphatase 1

Grants and funding

This work has been supported by grants from the Spanish Ministry of Education and Science SAF2011-27442 and a grant from Generalitat Valenciana (PrometeoII/2014/029). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.