Effects of Ser16 Phosphorylation on the Allosteric Transitions of Phospholamban/Ca2+-ATPase Complex

N. J. Traaseth, D. D. Thomas, G. Veglia

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43 Scopus citations


Phosphorylation by protein kinase A and dephosphorylation by protein phosphatase 1 modulate the inhibitory activity of phospholamban (PLN), the endogenous regulator of the sarco(endo)plasmic reticulum calcium Ca2+ ATPase (SERCA). This cyclic mechanism constitutes the driving force for calcium reuptake from the cytoplasm into the myocite lumen, regulating cardiac contractility. PLN undergoes a conformational transition between a relaxed (R) and tense (T) state, an equilibrium perturbed by the addition of SERCA. Here, we show that the single phosphoryl transfer at Ser16 induces a more pronounced conformational switch to the R state in phosphorylated PLN (pPLN). The binding affinity of PLN to SERCA is not affected (Kd values for the transmembrane domains of pPLN and PLN are ∼60 μM), supporting the hypothesis that phosphorylation at Ser16 does not dissociate PLN from SERCA. However, the binding surface and dynamics in domain Ib (residues 22-31) change substantially upon phosphorylation. Since PLN can be singly or doubly phosphorylated at Ser16 and Thr17, we propose that these sites remotely control the conformation of domain Ib. These findings constitute a paradigm for how post-translational modifications such as phosphorylation in the cytoplasmic portion of membrane proteins control intramembrane protein-protein interactions.

Original languageEnglish (US)
Pages (from-to)1041-1050
Number of pages10
JournalJournal of Molecular Biology
Issue number4
StatePublished - May 12 2006

Bibliographical note

Funding Information:
This work was supported by National Institute of Health grants GM27906 (to D.D.T.) and HL080081 and GM64742 (to G.V.) and American Heart Association grant 0160465Z. N.J.T. is supported by an American Heart Association Greater Midwest Affiliate Pre-Doctoral fellowship (0515491Z). We thank Jarrod Buffy for helpful discussion; Chikashi Toyoshima and David MacLennan for coordinates of the PLN/SERCA model; Emily Metcalfe, Jamillah Zamoon, and Florentin Nitu for technical assistance. NMR instrumentation at the University of Minnesota High Field NMR Center was funded by the National Science Foundation (BIR-961477) and the University of Minnesota Medical School.


  • NMR
  • detergent micelles
  • phospholamban
  • phosphorylated phospholamban


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