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

Fisher, M'Lynn E; Bovo, Elisa; Aguayo‐Ortiz, Rodrigo; Cho, Ellen E.; Pribadi, Marsha P.; Dalton, Michael P.; Rathod, Nishadh; Lemieux, M. Joanne; Espinoza-Fonseca, L. Michel; Robia, Seth L.; Zima, Aleksey V.; Young, Howard S.

doi:10.7554/elife.65545

Cited by 34 publications

(69 citation statements)

References 68 publications

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“…2H and I), consistent with enhanced DWORF-SERCA binding affinity at elevated cytoplasmic Ca 2+ (Fig. 2E) (4).…”

Section: Serca Affinity For Plb and Dworf Is Dependent On Ca 2+ -Pump Conformationsupporting

confidence: 77%

“…Importantly, PLB-SERCA complexes do not dissociate en masse during systole (Fig. 4D); we have previously reported that elevated Ca 2+ causes only small shifts in regulatory complex binding equilibria (4,22). Still, cardiac Ca 2+ transients simultaneously reduce PLB binding affinity and favor DWORF binding, driving a "dynamic fraction" of the population of these micropeptides to exchange from SERCA during each Ca 2+ transient.…”

Section: Discussionmentioning

confidence: 75%

“…Thus, PLB may be considered a subunit of SERCA, and the mechanism for relief of inhibition must be due to some other structural rearrangement of the intact PLB-SERCA complex (24). We have previously shown that Ca 2+ -dependent shifts in SERCA conformational poise alter the apparent affinity of SERCA for PLB (4, 22, 25). We hypothesize PLB must bind more tightly to certain SERCA conformations, and this may be a key aspect of its regulatory function.…”

Section: Introductionmentioning

confidence: 99%

“…Regulatory interactions of SERCA (gray) with PLB (blue) and DWORF (red). Structures: PLB 5 – PDB:2KYV (1); PLB 1 – PDB:1FJP, (2); PLB-SERCA, DWORF-SERCA (3, 4); DWORF-7MPA, (5). …”

Section: Introductionmentioning

confidence: 99%

“…1 , red) (5). In contrast to inhibitory PLB, DWORF has been proposed to increase Ca 2+ transport in the heart by competing with PLB for its binding site on SERCA, relieving inhibition (30, 31), and it may also directly stimulate the pump (4, 32). We previously observed that DWORF has low oligomerization affinity, but DWORF and PLB have similar affinity for SERCA (33, 34).…”

Section: Introductionmentioning

confidence: 99%

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Inhibitory and Stimulatory Micropeptides Preferentially Bind to Different Conformations of the Cardiac Calcium Pump

Cleary

Fang

et al. 2021

Preprint

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The ATP-dependent ion pump SERCA sequesters Ca2+ in the endoplasmic reticulum to establish a reservoir for cell signaling. Because of its central importance in physiology, this transporter is tightly controlled by physical interactions with tissue-specific regulatory micropeptides that tune SERCA function to match changing physiological conditions. In the heart, phospholamban (PLB) inhibits SERCA, while dwarf open reading frame (DWORF) stimulates SERCA. These competing interactions determine cardiac performance by modulating the amplitude of Ca2+ signals that drive the contraction/relaxation cycle. The distinct functions of these peptides may relate to their reciprocal preferences for SERCA binding. While SERCA binds PLB more avidly at low cytoplasmic Ca2+, it binds DWORF better at high Ca2+. In the present study, we determined that this opposing Ca2+ sensitivity is due to preferential binding of DWORF and PLB to different intermediate conformations that the pump samples during the Ca2+ transport cycle. The results suggest a mechanistic basis for inhibitory and stimulatory micropeptide function. In addition, fluorescence resonance energy transfer (FRET) measurements revealed dynamic shifts in SERCA-micropeptide binding equilibria during cellular Ca2+ elevations. The data suggest Ca2+-dependent dynamic exchange of inhibitory and stimulatory micropeptides from SERCA during the cardiac cycle. Together, these mechanisms provide beat-to-beat modulation of cardiac Ca2+ handling and contribute to the heart's adaptation to the increased physiological demands of exercise.

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“…2H and I), consistent with enhanced DWORF-SERCA binding affinity at elevated cytoplasmic Ca 2+ (Fig. 2E) (4).…”

Section: Serca Affinity For Plb and Dworf Is Dependent On Ca 2+ -Pump Conformationsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

“…Regulatory interactions of SERCA (gray) with PLB (blue) and DWORF (red). Structures: PLB 5 – PDB:2KYV (1); PLB 1 – PDB:1FJP, (2); PLB-SERCA, DWORF-SERCA (3, 4); DWORF-7MPA, (5). …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Inhibitory and Stimulatory Micropeptides Preferentially Bind to Different Conformations of the Cardiac Calcium Pump

Cleary

Fang

et al. 2021

Preprint

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Microproteins in skeletal muscle: hidden keys in muscle physiology

Bonilauri

Dallagiovanna

2021

J cachexia sarcopenia muscle

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Recent advances in the transcriptomics, translatomics, and proteomics have led us to the exciting new world of functional endogenous microproteins. These microproteins have a small size and are derived from small open reading frames (smORFs) of RNAs previously annotated as non-coding (e.g. lncRNAs and circRNAs) as well as from untranslated regions and canonical mRNAs. The presence of these microproteins reveals a much larger translatable portion of the genome, shifting previously defined dogmas and paradigms. These findings affect our view of organisms as a whole, including skeletal muscle tissue. Emerging evidence demonstrates that several smORF-derived microproteins play crucial roles during muscle development (myogenesis), maintenance, and regeneration, as well as lipid and glucose metabolism and skeletal muscle bioenergetics. These microproteins are also involved in processes including physical activity capacity, cellular stress, and muscular-related diseases (i.e. myopathy, cachexia, atrophy, and muscle wasting). Given the role of these small proteins as important key regulators of several skeletal muscle processes, there are rich prospects for the discovery of new microproteins and possible therapies using synthetic microproteins.

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Microproteins—Discovery, structure, and function

Mohsen,

Martel,

Slavoff

2023

Proteomics

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Advances in proteogenomic technologies have revealed hundreds to thousands of translated small open reading frames (sORFs) that encode microproteins in genomes across evolutionary space. While many microproteins have now been shown to play critical roles in biology and human disease, a majority of recently identified microproteins have little or no experimental evidence regarding their functionality. Computational tools have some limitations for analysis of short, poorly conserved microprotein sequences, so additional approaches are needed to determine the role of each member of this recently discovered polypeptide class. A currently underexplored avenue in the study of microproteins is structure prediction and determination, which delivers a depth of functional information. In this review, we provide a brief overview of microprotein discovery methods, then examine examples of microprotein structures (and, conversely, intrinsic disorder) that have been experimentally determined using crystallography, cryo‐electron microscopy, and NMR, which provide insight into their molecular functions and mechanisms. Additionally, we discuss examples of predicted microprotein structures that have provided insight or context regarding their function. Analysis of microprotein structure at the angstrom level, and confirmation of predicted structures, therefore, has potential to identify translated microproteins that are of biological importance and to provide molecular mechanism for their in vivo roles.

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

Cited by 34 publications

References 68 publications

Inhibitory and Stimulatory Micropeptides Preferentially Bind to Different Conformations of the Cardiac Calcium Pump

Inhibitory and Stimulatory Micropeptides Preferentially Bind to Different Conformations of the Cardiac Calcium Pump

Microproteins in skeletal muscle: hidden keys in muscle physiology

Microproteins—Discovery, structure, and function

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