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


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 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.

SUBMITTER: Larsen EK 

PROVIDER: S-EPMC6899184 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Intrinsically disordered HAX-1 regulates Ca<sup>2+</sup> cycling by interacting with lipid membranes and the phospholamban cytoplasmic region.

Larsen Erik K EK   Weber Daniel K DK   Wang Songlin S   Gopinath Tata T   Blackwell Daniel J DJ   Dalton Michael P MP   Robia Seth L SL   Gao Jiali J   Veglia Gianluigi G  

Biochimica et biophysica acta. Biomembranes 20190807 1


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<sup>2+</sup> 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 mechani  ...[more]

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