Abstract
The endoplasmic reticulum (ER) is the reservoir for calcium in cells. Luminal calcium levels are determined by calcium-sensing proteins that trigger calcium dynamics in response to calcium fluctuations. Here we report that Selenoprotein N (SEPN1) is a type II transmembrane protein that senses ER calcium fluctuations by binding this ion through a luminal EF-hand domain. In vitro and in vivo experiments show that via this domain, SEPN1 responds to diminished luminal calcium levels, dynamically changing its oligomeric state and enhancing its redox-dependent interaction with cellular partners, including the ER calcium pump sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). Importantly, single amino acid substitutions in the EF-hand domain of SEPN1 identified as clinical variations are shown to impair its calcium-binding and calcium-dependent structural changes, suggesting a key role of the EF-hand domain in SEPN1 function. In conclusion, SEPN1 is a ER calcium sensor that responds to luminal calcium depletion, changing its oligomeric state and acting as a reductase to refill ER calcium stores.
Highlights
The endoplasmic reticulum (ER) is the reservoir for calcium in cells
Our results suggest that SEPN1 regulates the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA)-mediated replenishment of ER calcium stores, a crucial mechanism for excitation-contraction coupling in skeletal muscle
It presents in infancy with heterogeneous clinical manifestations ranging from mild myopathy to severe muscle weakness that can lead to death due to respiratory failure [27]
Summary
The endoplasmic reticulum (ER) is the reservoir for calcium in cells. Luminal calcium levels are determined by calcium-sensing proteins that trigger calcium dynamics in response to calcium fluctuations. Through the EF-hand domain, STIM1 senses the reduced calcium luminal level that occurs in skeletal muscle during excitation-contraction coupling and activates store-operated calcium entry (SOCE), increasing ER uptake of calcium from the extracellular space [13, 14]. While this phenomenon is key for the ER/SR to retrieve calcium from the extracellular space, cells, and muscle cells, must be able to rapidly restore basal low cytosolic calcium concentrations to allow the contractile. The activity of both the SERCA pump and IP3R and RYR are regulated by redox, indicating a cross-talk between the redox state of calcium handling proteins and their activity in regulating luminal calcium levels [5, 9,10,11,12]
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