Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation

Elife. 2021 May 12;10:e66226. doi: 10.7554/eLife.66226.


Phospholamban (PLN) is a mini-membrane protein that directly controls the cardiac Ca2+-transport response to β-adrenergic stimulation, thus modulating cardiac output during the fight-or-flight response. In the sarcoplasmic reticulum membrane, PLN binds to the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), keeping this enzyme's function within a narrow physiological window. PLN phosphorylation by cAMP-dependent protein kinase A or increase in Ca2+ concentration reverses the inhibitory effects through an unknown mechanism. Using oriented-sample solid-state NMR spectroscopy and replica-averaged NMR-restrained structural refinement, we reveal that phosphorylation of PLN's cytoplasmic regulatory domain signals the disruption of several inhibitory contacts at the transmembrane binding interface of the SERCA-PLN complex that are propagated to the enzyme's active site, augmenting Ca2+ transport. Our findings address long-standing questions about SERCA regulation, epitomizing a signal transduction mechanism operated by posttranslationally modified bitopic membrane proteins.

Keywords: E. coli; membrane proteins; molecular biophysics; oriented solid; state NMR; structural biology; topological allostery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation*
  • Animals
  • Calcium / metabolism
  • Calcium-Binding Proteins / chemistry*
  • Calcium-Binding Proteins / metabolism
  • Escherichia coli
  • Magnetic Resonance Spectroscopy
  • Membrane Proteins / metabolism
  • Molecular Structure
  • Phosphorylation*
  • Protein Conformation
  • Rabbits
  • Sarcoplasmic Reticulum
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / chemistry*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Signal Transduction


  • Calcium-Binding Proteins
  • Membrane Proteins
  • phospholamban
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium