Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCA.
Calcium
/ metabolism
Calcium Signaling
Calcium-Binding Proteins
/ metabolism
Enzyme Activation
HEK293 Cells
Humans
Molecular Dynamics Simulation
Peptides
/ chemistry
Protein Conformation
Sarcoplasmic Reticulum
/ enzymology
Sarcoplasmic Reticulum Calcium-Transporting ATPases
/ chemistry
Structure-Activity Relationship
Time Factors
biochemistry
calcium ATPase
cellular calcium dynamics
chemical biology
fluorescence resonance energy transfer
membrane reconstitution
molecular dynamics simulations
none
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
02 06 2021
02 06 2021
Historique:
received:
07
12
2020
accepted:
01
06
2021
pubmed:
3
6
2021
medline:
21
10
2021
entrez:
2
6
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34075877
doi: 10.7554/eLife.65545
pii: 65545
pmc: PMC8203291
doi:
pii:
Substances chimiques
Calcium-Binding Proteins
0
DWORF peptide, human
0
Peptides
0
phospholamban
0
Sarcoplasmic Reticulum Calcium-Transporting ATPases
EC 3.6.3.8
Calcium
SY7Q814VUP
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL130231
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139065
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL143816
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM120142
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL148068
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL092321
Pays : United States
Informations de copyright
© 2021, Fisher et al.
Déclaration de conflit d'intérêts
MF, EB, RA, EC, MP, MD, NR, LE, SR, AZ, HY No competing interests declared, ML Reviewing editor, eLife
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