Intrinsically disordered HAX-1 regulates Ca2+ cycling by interacting with lipid membranes and the phospholamban cytoplasmic region

Erik K. Larsen, Daniel K. Weber, Songlin Wang, Tata Gopinath, Daniel J. Blackwell, Michael P. Dalton, Seth L. Robia, Jiali Gao, Gianluigi Veglia

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Hematopoietic-substrate-1 associated protein X-1 (HAX-1) is a 279 amino acid protein expressed ubiquitously. In cardiac muscle, HAX-1 was found to modulate the sarcoendoplasmic reticulum calcium ATPase (SERCA) by shifting its apparent Ca2+ affinity (pCa). It has been hypothesized that HAX-1 binds phospholamban (PLN), enhancing its inhibitory function on SERCA. HAX-1 effects are reversed by cAMP-dependent protein kinase A that phosphorylates PLN at Ser16. To date, the molecular mechanisms for HAX-1 regulation of the SERCA/PLN complex are still unknown. Using enzymatic, in cell assays, circular dichroism, and NMR spectroscopy, we found that in the absence of a binding partner HAX-1 is essentially disordered and adopts a partial secondary structure upon interaction with lipid membranes. Also, HAX-1 interacts with the cytoplasmic region of monomeric and pentameric PLN as detected by NMR and in cell FRET assays, respectively. We propose that the regulation of the SERCA/PLN complex by HAX-1 is mediated by its interactions with lipid membranes, adding another layer of control in Ca2+ homeostatic balance in the heart muscle.

Original languageEnglish (US)
Article number183034
JournalBiochimica et Biophysica Acta - Biomembranes
Issue number1
StatePublished - Jan 1 2020



  • HAX-1
  • Intrinsically disordered proteins
  • NMR spectroscopy
  • Phospholamban
  • Protein-membrane interactions

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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