Inhibitory and stimulatory micropeptides preferentially bind to different conformations of the cardiac calcium pump

Abstract

The ATP-dependent ion pump sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) sequesters Ca2+ in the endoplasmic reticulum to establish a reservoir for cell signaling. Because of its central importance in physiology, the activity of this transporter is tightly controlled via direct interactions with tissue-specific regulatory micropeptides that tune SERCA function to match changing physiological conditions. In the heart, the micropeptide 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. We hypothesized that the functions of these peptides may relate to their reciprocal preferences for SERCA binding; SERCA binds PLB more avidly at low cytoplasmic [Ca2+] but binds DWORF better when [Ca2+] is high. In the present study, we demonstrated this opposing Ca2+ sensitivity is due to preferential binding of DWORF and PLB to different intermediate states that SERCA samples during the Ca2+ transport cycle. We show PLB binds best to the SERCA E1-ATP state, which prevails at low [Ca2+]. In contrast, DWORF binds most avidly to E1P and E2P states that are more populated when Ca2+ is elevated. Moreover, FRET microscopy revealed dynamic shifts in SERCA–micropeptide binding equilibria during cellular Ca2+ elevations. A computational model showed that DWORF exaggerates changes in PLB–SERCA binding during the cardiac cycle. These results suggest a mechanistic basis for inhibitory versus stimulatory micropeptide function, as well as a new role for DWORF as a modulator of dynamic oscillations of PLB–SERCA regulatory interactions. The ATP-dependent ion pump sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) sequesters Ca2+ in the endoplasmic reticulum to establish a reservoir for cell signaling. Because of its central importance in physiology, the activity of this transporter is tightly controlled via direct interactions with tissue-specific regulatory micropeptides that tune SERCA function to match changing physiological conditions. In the heart, the micropeptide 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. We hypothesized that the functions of these peptides may relate to their reciprocal preferences for SERCA binding; SERCA binds PLB more avidly at low cytoplasmic [Ca2+] but binds DWORF better when [Ca2+] is high. In the present study, we demonstrated this opposing Ca2+ sensitivity is due to preferential binding of DWORF and PLB to different intermediate states that SERCA samples during the Ca2+ transport cycle. We show PLB binds best to the SERCA E1-ATP state, which prevails at low [Ca2+]. In contrast, DWORF binds most avidly to E1P and E2P states that are more populated when Ca2+ is elevated. Moreover, FRET microscopy revealed dynamic shifts in SERCA–micropeptide binding equilibria during cellular Ca2+ elevations. A computational model showed that DWORF exaggerates changes in PLB–SERCA binding during the cardiac cycle. These results suggest a mechanistic basis for inhibitory versus stimulatory micropeptide function, as well as a new role for DWORF as a modulator of dynamic oscillations of PLB–SERCA regulatory interactions. The type 2a sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA2a) is a P-type ion transporter responsible for sequestering cytoplasmic Ca2+ into the sarcoplasmic reticulum (SR) of cardiac muscle cells. The rate of Ca2+ transport by SERCA2a determines how quickly the heart muscle relaxes during the diastolic phase of the cardiac cycle as the ventricle is filling with blood. SERCA2a function also sets the amplitude of SR Ca2+ release, which determines the heart’s contractile strength during the systolic phase when blood is being ejected from the heart. Pathological decreases in SERCA expression, function, and regulation are associated with heart failure (1Currie S. Smith G. Enhanced phosphorylation of phospholamban and downregulation of sarco/endoplasmic reticulum Ca ATPase type 2 (SERCA 2) in cardiac sarcoplasmic reticulum from rabbits with heart failure.Cardiovasc. Res. 1999; 41: 135-146Crossref PubMed Scopus (81) Google Scholar, 2Hasenfuss G. Reinecke H. Studer R. Meyer M. Pieske B. Holtz J. et al.Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+-ATPase in failing and nonfailing human myocardium.Circ. Res. 1994; 75: 434-442Crossref PubMed Scopus (660) Google Scholar), focusing attention on SERCA as a possible therapeutic target (3Hayward C. Banner N.R. Morley-Smith A. Lyon A.R. Harding S.E. The current and of SERCA for heart a PubMed Scopus Google Scholar, of cardiac by the Res. PubMed Scopus Google to transport function in by expression of SERCA2a with B. J. et by of in with cardiac a phase PubMed Scopus Google is in physiological SERCA regulatory to a that the function of the SERCA in with heart The of SERCA function in the heart is phospholamban a micropeptide PLB with SERCA and its for Ca2+ G. of cardiac and sarcoplasmic reticulum of a phospholamban on by PubMed Google is at of cytoplasmic Ca2+ and phosphorylation of PLB by M. of a of the cardiac sarcoplasmic reticulum by PubMed Google Scholar, R. A. of a and its to transport in sarcoplasmic reticulum from PubMed Scopus Google Scholar), a to Ca2+ transport in to and the of SERCA to of the PLB–SERCA PLB phosphorylation Ca2+ binding to SERCA M. M. interactions between phospholamban and reticulum are by but by phospholamban and are by PubMed Scopus Google Scholar, M. M. M. and of phospholamban regulation of the Ca2+ pump of sarcoplasmic PubMed Scopus Google Scholar, C. M. R. of the inhibitory of phospholamban with the Ca2+ S. A. PubMed Scopus Google Scholar, Ca2+ binding to of the cardiac Ca2+ pump is to PubMed Scopus Google Scholar, between of phospholamban and of the cardiac Ca2+ pump revealed by PubMed Scopus Google showed that the PLB–SERCA PLB phosphorylation in Ca2+ in phospholamban to PubMed Scopus Google Scholar, M. R. et regulation of SERCA by of S. A. PubMed Scopus Google Scholar), that PLB more a of a SERCA regulatory These may by that SERCA binds PLB with in Ca2+ binds with to pump PubMed Scopus Google Scholar, and suggest on the SERCA PubMed Scopus Google Scholar, R. et open reading frame (DWORF) is a direct of the sarcoplasmic reticulum pump PubMed Scopus Google PLB more tightly to SERCA that at low Ca2+ and avidly to SERCA states that at the of PLB binding to SERCA In the present study, we PLB–SERCA interactions in cell to the of PLB for different intermediate states in the Ca2+ transport cycle. In to direct regulation by PLB inhibitory may by of PLB into PLB M. inhibitory function is by PubMed Scopus Google that as a and the of may by PLB are by PLB phosphorylation phospholamban and the of its regulatory PubMed Scopus Google Scholar, and phosphorylation the of phospholamban in PubMed Scopus Google Scholar, S. J. of and its with the PubMed Scopus Google The at which PLB between and how quickly these in We that phospholamban from but from the SERCA regulatory Res. PubMed Scopus Google and A. M. in the by phospholamban PubMed Scopus Google that the of PLB from to from the SERCA regulatory but the of these binding the to which these regulatory may in the cardiac SR PLB for SERCA binding with micropeptide in the heart, dwarf open reading frame (DWORF) S. A. S. G. A in DWORF the of the sarcoplasmic reticulum PubMed Scopus Google Scholar), in in In to DWORF stimulates SERCA activity R. et open reading frame (DWORF) is a direct of the sarcoplasmic reticulum pump PubMed Scopus Google Scholar, A. The DWORF SERCA2a via PubMed Scopus Google and the inhibitory PLB S. et DWORF micropeptide and heart failure in a model of PubMed Google Scholar, J. et micropeptide of SERCA but to the pump as PubMed Scopus Google Scholar, et by a as SERCA activity in PubMed Scopus Google Scholar, S. R. with the DWORF micropeptide in Res. PubMed Scopus Google showed that to DWORF for SERCA with Ca2+ R. et open reading frame (DWORF) is a direct of the sarcoplasmic reticulum pump PubMed Scopus Google dynamic of stimulatory and inhibitory Ca2+ DWORF binding to SERCA, but PLB more as Ca2+ we the dynamic binding of DWORF and PLB to SERCA during cellular Ca2+ oscillations to how the of micropeptides may for We FRET to shifts in the PLB–SERCA binding in cardiac binds with to pump PubMed Scopus Google and interactions with a of and in that we a more model that cardiac We these with a computational model that rate mechanistic into how regulatory equilibria during the cardiac on a how Ca2+ may between and The results may to therapeutic on of micropeptides S. et DWORF micropeptide and heart failure in a model of PubMed Google Scholar, S. R. with the DWORF micropeptide in Res. PubMed Scopus Google Scholar, of DWORF open reading in and PubMed Scopus Google We demonstrated that PLB–SERCA binding is in to a of the is more with [Ca2+] binds with to pump PubMed Scopus Google Scholar, R. et open reading frame (DWORF) is a direct of the sarcoplasmic reticulum pump PubMed Scopus Google reciprocal Ca2+ the that PLB and DWORF may to different intermediate of the SERCA cycle. The SERCA cycle of PubMed Scopus Google is in Ca2+ SERCA in the state, E1-ATP B. J. of the PubMed Scopus Google for Ca2+ to Ca2+ SERCA samples the intermediate states of the Ca2+ transport but these states are populated during is in the that in its cycle of the and in the the Ca2+ of reticulum Ca2+-ATPase PubMed Scopus Google Scholar, J. B. 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