A hallmark of phospholamban functional divergence is located in the N-terminal phosphorylation domain

Eli Fernández-de Gortari, Rodrigo Aguayo-Ortiz, Joseph M. Autry, L. Michel Espinoza-Fonseca

Research output: Contribution to journalArticle

Abstract

Sarcoplasmic reticulum Ca2+ pump (SERCA) is a critical component of the Ca2+ transport machinery in myocytes. There is clear evidence for regulation of SERCA activity by PLB, whose activity is modulated by phosphorylation of its N-terminal domain (residues 1–25), but there is less clear evidence for the role of this domain in PLB's functional divergence. It is widely accepted that only sarcolipin (SLN), a protein that shares substantial homology with PLB, uncouples SERCA Ca2+ transport from ATP hydrolysis by inducing a structural change of its energy-transduction domain; yet, experimental evidence shows that the transmembrane domain of PLB (residues 26–52, PLB26–52) partially uncouples SERCA in vitro. These apparently conflicting mechanisms suggest that PLB's uncoupling activity is encoded in its transmembrane domain, and that it is controlled by the N-terminal phosphorylation domain. To test this hypothesis, we performed molecular dynamics simulations (MDS) of the binary complex between PLB26–52 and SERCA. Comparison between PLB26–52 and wild-type PLB (PLBWT) showed no significant changes in the stability and orientation of the transmembrane helix, indicating that PLB26–52 forms a native-like complex with SERCA. MDS showed that PLB26–52 produces key intermolecular contacts and structural changes required for inhibition, in agreement with studies showing that PLB26–52 inhibits SERCA. However, deletion of the N-terminal phosphorylation domain facilitates an order-to-disorder shift in the energy-transduction domain associated with uncoupling of SERCA, albeit weaker than that induced by SLN. This mechanistic evidence reveals that the N-terminal phosphorylation domain of PLB is a primary contributor to the functional divergence among homologous SERCA regulators.

Original languageEnglish (US)
Pages (from-to)705-713
Number of pages9
JournalComputational and Structural Biotechnology Journal
Volume18
DOIs
StatePublished - 2020

Keywords

  • Calcium pump
  • Functional divergence
  • Molecular dynamics simulations
  • Phospholamban
  • Phosphorylation domain
  • Sarcolipin

PubMed: MeSH publication types

  • Journal Article

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