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Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCA. 2021

M'Lynn E Fisher, and Elisa Bovo, and Rodrigo Aguayo-Ortiz, and Ellen E Cho, and Marsha P Pribadi, and Michael P Dalton, and Nishadh Rathod, and M Joanne Lemieux, and L Michel Espinoza-Fonseca, and Seth L Robia, and Aleksey V Zima, and Howard S Young
Department of Biochemistry, University of Alberta, Edmonton, Canada.

The sarco-plasmic reticulum calcium pump (SERCA) plays a critical role in the contraction-relaxation cycle of muscle. In cardiac muscle, SERCA is regulated by the inhibitor phospholamban. A new regulator, dwarf open reading frame (DWORF), has been reported to displace phospholamban from SERCA. Here, we show that DWORF is a direct activator of SERCA, increasing its turnover rate in the absence of phospholamban. Measurement of in-cell calcium dynamics supports this observation and demonstrates that DWORF increases SERCA-dependent calcium reuptake. These functional observations reveal opposing effects of DWORF activation and phospholamban inhibition of SERCA. To gain mechanistic insight into SERCA activation, fluorescence resonance energy transfer experiments revealed that DWORF has a higher affinity for SERCA in the presence of calcium. Molecular modeling and molecular dynamics simulations provide a model for DWORF activation of SERCA, where DWORF modulates the membrane bilayer and stabilizes the conformations of SERCA that predominate during elevated cytosolic calcium.

UI MeSH Term Description Entries
D010455 Peptides Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are considered to be larger versions of peptides that can form into complex structures such as ENZYMES and RECEPTORS. Peptide,Polypeptide,Polypeptides
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D002118 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D002135 Calcium-Binding Proteins Proteins to which calcium ions are bound. They can act as transport proteins, regulator proteins, or activator proteins. They typically contain EF HAND MOTIFS. Calcium Binding Protein,Calcium-Binding Protein,Calcium Binding Proteins,Binding Protein, Calcium,Binding Proteins, Calcium,Protein, Calcium Binding,Protein, Calcium-Binding
D004789 Enzyme Activation Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. Activation, Enzyme,Activations, Enzyme,Enzyme Activations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D012519 Sarcoplasmic Reticulum A network of tubules and sacs in the cytoplasm of SKELETAL MUSCLE FIBERS that assist with muscle contraction and relaxation by releasing and storing calcium ions. Reticulum, Sarcoplasmic,Reticulums, Sarcoplasmic,Sarcoplasmic Reticulums
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013997 Time Factors Elements of limited time intervals, contributing to particular results or situations. Time Series,Factor, Time,Time Factor
D053498 Sarcoplasmic Reticulum Calcium-Transporting ATPases Calcium-transporting ATPases that catalyze the active transport of CALCIUM into the SARCOPLASMIC RETICULUM vesicles from the CYTOPLASM. They are primarily found in MUSCLE CELLS and play a role in the relaxation of MUSCLES. Calcium-Transporting ATPases, Sarcoplasmic Reticulum,Sarcoplasmic Reticulum Calcium ATPase,SERCA Calcium ATPase,SERCA1 Calcium ATPase,SERCA2 Calcium ATPase,SERCA2a Calcium ATPase,SERCA3 Calcium ATPase,SR Ca(2+)-ATPase 1,SR Ca(2+)-ATPase 2,SR Ca(2+)-ATPase 3,Sarco-Endoplasmic Reticulum Ca2+-ATPase,Sarcoplasmic Reticulum Ca(2+)-ATPase,Sarcoplasmic Reticulum Calcium-Transporting ATPase 1,Sarcoplasmic Reticulum Calcium-Transporting ATPase 2,Sarcoplasmic Reticulum Calcium-Transporting ATPase 2a,Sarcoplasmic Reticulum Calcium-Transporting ATPase 3,Sarcoplasmic-Endoplasmic Reticulum Calcium ATPase 2,Sarcoplasmic-Endoplasmic Reticulum Calcium ATPase 2a,Sarcoplasmic-Endoplasmic Reticulum Calcium ATPase 3,Sarcoplasmic-endoplasmic Reticulum Calcium ATPase 1,Ca2+-ATPase, Sarco-Endoplasmic Reticulum,Calcium Transporting ATPases, Sarcoplasmic Reticulum,Reticulum Ca2+-ATPase, Sarco-Endoplasmic,Sarco Endoplasmic Reticulum Ca2+ ATPase,Sarcoplasmic Endoplasmic Reticulum Calcium ATPase 2,Sarcoplasmic Endoplasmic Reticulum Calcium ATPase 2a,Sarcoplasmic Endoplasmic Reticulum Calcium ATPase 3,Sarcoplasmic Reticulum Calcium Transporting ATPase 1,Sarcoplasmic Reticulum Calcium Transporting ATPase 2,Sarcoplasmic Reticulum Calcium Transporting ATPase 2a,Sarcoplasmic Reticulum Calcium Transporting ATPase 3,Sarcoplasmic Reticulum Calcium Transporting ATPases,Sarcoplasmic endoplasmic Reticulum Calcium ATPase 1

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