1. Intrinsically disordered HAX-1 regulates Ca 2+ cycling by interacting with lipid membranes and the phospholamban cytoplasmic region.
- Author
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Larsen EK, Weber DK, Wang S, Gopinath T, Blackwell DJ, Dalton MP, Robia SL, Gao J, and Veglia G
- Subjects
- Adaptor Proteins, Signal Transducing chemistry, Animals, Calcium-Binding Proteins ultrastructure, Humans, Intrinsically Disordered Proteins, Magnetic Resonance Spectroscopy, Protein Structure, Secondary, Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism, Adaptor Proteins, Signal Transducing physiology, Calcium metabolism, Calcium-Binding Proteins metabolism, Cytoplasm metabolism, Membrane Lipids metabolism, Myocardium metabolism
- Abstract
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 Ca
2+ 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., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2020
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