{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have revealed that the small transmembrane peptide DWORF directly stimulates the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) by binding to specific conformations of the pump, thereby accelerating its Ca2+ transport activity and promoting rapid calcium reuptake. This activation not only counteracts the inhibitory effects of phospholamban (PLB) on SERCA but also enhances the overall turnover rate of SERCA in cardiac muscle, which is crucial for efficient contraction-relaxation cycles. These findings were supported by molecular modeling, in‐cell calcium measurements, and FRET-based binding studies that demonstrated a higher affinity of DWORF for SERCA when cytosolic Ca2+ was elevated."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nComplementary cell-based FRET biosensor experiments further revealed that DWORF competes with PLB for binding to SERCA, thereby diminishing the inhibitory impact of PLB. Intriguingly, DWORF was also shown to enhance SERCA’s enzymatic function in the absence of PLB under subsaturating calcium conditions—a function that was negated when key residues (P15 and W22) were mutated. This not only confirms DWORF’s role as an activator of SERCA but also highlights the molecular determinants for its effective interaction with the Ca2+-pump."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, detailed FRET microscopy and computational modeling studies have provided insights into the dynamic nature of SERCA regulation by DWORF. Whereas PLB preferentially binds to the SERCA E1-ATP state (predominant at low cytosolic Ca2+), DWORF shows increased binding affinity for the E1P and E2P states that are more populated when Ca2+ levels are high. Such reciprocal binding dynamics not only facilitate rapid shifts in SERCA regulation during the cardiac cycle but also suggest that DWORF acts as a key modulator of the oscillatory interactions between PLB and SERCA, thereby fine-tuning cardiac calcium handling and contractility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "M'Lynn E Fisher, Elisa Bovo, Rodrigo Aguayo-Ortiz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.65545"}], "href": "https://doi.org/10.7554/eLife.65545"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34075877"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34075877"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ang Li, Samantha L Yuen, Daniel R Stroik, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The transmembrane peptide DWORF activates SERCA2a via dual mechanisms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbc.2021.100412"}], "href": "https://doi.org/10.1016/j.jbc.2021.100412"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33581112"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33581112"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Sean R Cleary, Xuan Fang, Ellen E Cho, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibitory and stimulatory micropeptides preferentially bind to different conformations of the cardiac calcium pump."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbc.2022.102060"}], "href": "https://doi.org/10.1016/j.jbc.2022.102060"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35605666"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35605666"}]}]}]}