Identification of a protein phosphatase-1/phospholamban complex that is regulated by cAMP-dependent phosphorylation

Elizabeth Vafiadaki, Demetrios A. Arvanitis, Despina Sanoudou, Evangelia G. Kranias

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

In human and experimental heart failure, the activity of the type 1 phosphatase is significantly increased, associated with dephosphorylation of phospholamban, inhibition of the sarco(endo)plasmic reticulum Ca2+ transport ATPase (SERCA2a) and depressed function. In the current study, we investigated the molecular mechanisms controlling protein phosphatase-1 activity. Using recombinant proteins and complementary in vitro binding studies, we identified a multi-protein complex centered on protein phosphatase-1 that includes its muscle specific glycogen-targeting subunit GM and substrate phospholamban. GM interacts directly with phospholamban and this association is mediated by the cytosolic regions of the proteins. Our findings suggest the involvement of GM in mediating formation of the phosphatase-1/GM/phospholamban complex through the direct and independent interactions of GM with both protein phosphatase-1 and phospholamban. Importantly, the protein phosphatase-1/GM/ phospholamban complex dissociates upon protein kinase A phosphorylation, indicating its significance in the β-adrenergic signalling axis. Moreover, protein phosphatase-1 activity is regulated by two binding partners, inhibitor-1 and the small heat shock protein 20, Hsp20. Indeed, human genetic variants of inhibitor-1 (G147D) or Hsp20 (P20L) result in reduced binding and inhibition of protein phosphatase-1, suggesting aberrant enzymatic regulation in human carriers. These findings provide insights into the mechanisms underlying fine-tuned regulation of protein phosphatase-1 and its impact on the SERCA2/phospholamban interactome in cardiac function.

Original languageEnglish
Article numbere80867
JournalPLoS One
Volume8
Issue number11
DOIs
Publication statusPublished - 14 Nov 2013
Externally publishedYes

Fingerprint

Protein Phosphatase 1
phosphoprotein phosphatase
Phosphorylation
phosphorylation
Phosphoric Monoester Hydrolases
HSP20 Heat-Shock Proteins
Small Heat-Shock Proteins
multiprotein complexes
Reticulum
cAMP-dependent protein kinase
Calcium-Transporting ATPases
dephosphorylation
Medical Genetics
heart failure
cardiac output
Cyclic AMP-Dependent Protein Kinases
phospholamban
Glycogen
heat shock proteins
Recombinant Proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Identification of a protein phosphatase-1/phospholamban complex that is regulated by cAMP-dependent phosphorylation. / Vafiadaki, Elizabeth; Arvanitis, Demetrios A.; Sanoudou, Despina; Kranias, Evangelia G.

In: PLoS One, Vol. 8, No. 11, e80867, 14.11.2013.

Research output: Contribution to journalArticle

Vafiadaki, Elizabeth ; Arvanitis, Demetrios A. ; Sanoudou, Despina ; Kranias, Evangelia G. / Identification of a protein phosphatase-1/phospholamban complex that is regulated by cAMP-dependent phosphorylation. In: PLoS One. 2013 ; Vol. 8, No. 11.
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