Functional and Structural Insights into Sarcolipin, a Regulator of the Sarco-Endoplasmic Reticulum Ca2+-ATPases

Barbot, Thomas; Montigny, Cédric; Decottignies, Paulette; Maire, Marc le; Jaxel, Christine; Jamin, Nadège; Beswick, Véronica

doi:10.1007/978-3-319-24780-9_10

Cited by 10 publications

(19 citation statements)

References 110 publications

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“…Presently it is unclear whether muscle NST in birds also involves Ca 2+ slippage controlled by SLN. However, the involvement of SLN in muscle NST in birds seem unlikely, since the C-terminus, which appears crucial for the regulation of SERCA (Barbot et al, 2016 ), has a differing amino acid-sequence (KSYQE/Q instead of RSYQY) (Montigny et al, 2014 ). Interestingly, a study on ducklings found that muscle NST was correlated to changes in avian UCP, a paralog of the mammalian UCP1, (the UCP1-locus has been lost in birds, Emre et al, 2007 ), which—in contrast to mammalian UCP1—is not associated with a change in mitochondrial membrane conductance, but involved in muscle thermogenesis.…”

Section: Non-shivering Thermogenesis In Muscle: How Does It Work?mentioning

confidence: 99%

Muscle Non-shivering Thermogenesis and Its Role in the Evolution of Endothermy

et al. 2017

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The development of sustained, long-term endothermy was one of the major transitions in the evolution of vertebrates. Thermogenesis in endotherms does not only occur via shivering or activity, but also via non-shivering thermogenesis (NST). Mammalian NST is mediated by the uncoupling protein 1 in the brown adipose tissue (BAT) and possibly involves an additional mechanism of NST in skeletal muscle. This alternative mechanism is based on Ca 2+ -slippage by a sarcoplasmatic reticulum Ca 2+ -ATPase (SERCA) and is controlled by the protein sarcolipin. The existence of muscle based NST has been discussed for a long time and is likely present in all mammals. However, its importance for thermoregulation was demonstrated only recently in mice. Interestingly, birds, which have evolved from a different reptilian lineage than mammals and lack UCP1-mediated NST, also exhibit muscle based NST under the involvement of SERCA, though likely without the participation of sarcolipin. In this review we summarize the current knowledge on muscle NST and discuss the efficiency of muscle NST and BAT in the context of the hypothesis that muscle NST could have been the earliest mechanism of heat generation during cold exposure in vertebrates that ultimately enabled the evolution of endothermy. We suggest that the evolution of BAT in addition to muscle NST was related to heterothermy being predominant among early endothermic mammals. Furthermore, we argue that, in contrast to small mammals, muscle NST is sufficient to maintain high body temperature in birds, which have enhanced capacities to fuel muscle NST by high rates of fatty acid import.

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Section: Non-shivering Thermogenesis In Muscle: How Does It Work?mentioning

confidence: 99%

Muscle Non-shivering Thermogenesis and Its Role in the Evolution of Endothermy

et al. 2017

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“…Previous work has shown SLN mRNA and/or protein levels to be several magnitudes higher in both slow and fast twitch skeletal muscles of rabbits, pigs, dogs, and humans than lab rodents, leading to suggestions that SLN-NST may be of greater thermogenic importance in larger mammals (Barbot et al, 2016 ). However, given that larger mammals also possess lower surface-area-to-volume ratios, thicker insulation, and the ability to further minimize heat loss via countercurrent heat exchangers, this contention is puzzling.…”

Section: Sln Expression and Evolutionary Analysesmentioning

confidence: 99%

“…To our knowledge, no studies have yet demonstrated that SLN-NST can be activated/inactivated independently from muscle contraction, let alone have identified the molecular mechanism by which this process can be mediated. While phosphorylation of one or more residues (Ser 4 and/or Thr 5 ) within the cytosolic domain have been shown to relieve the inhibitory effect of SLN on cardiac SERCA pumps (Gramolini et al, 2004 ; Bhupathy et al, 2009 ), likely via structural changes to the SLN-SERCA complex, it remains unknown whether this mechanism alters uncoupling activity (Autry et al, 2016 ; Barbot et al, 2016 ). However, primary sequence analysis of available data reveal that either one or both of Ser 4 and Thr 5 are—with one exception (equids)—universally present from fish to mammals (Barbot et al, 2016 ; Gaudry et al, 2017 ), indicating that this inhibitory mechanism of control is likely both ancient and highly conserved.…”

Section: How Is Sln Regulated?mentioning

confidence: 99%

Sarcolipin Makes Heat, but Is It Adaptive Thermogenesis?

Campbell

Dicke

2018

Front. Physiol.

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“…However, TNPAMP, the ATP analog in these crystal structures, is not close to T353 and T625 in 3w5b Remarkably, in these structures, the P-N linker adopts a helix structure accompanied by the curvature of TM5 and the kink of TM6, as in 3w5b (SERCA1a.Mg 2+ ) and our energy-minimized E1.Mg 2+ structure. These local modifications around the phosphorylation site, may slightly slow down the ATP hydrolysis rate as observed in (18,(64)(65)(66)(67)(68)(69)(70)(71)(72).…”

Section: Discussionmentioning

confidence: 96%

Deciphering the mechanism of inhibition of SERCA1a by sarcolipin using molecular simulations

Barbot

Beswick

Montigny

et al. 2019

Preprint

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SERCA1a is an ATPase calcium pump that transports Ca 2+ from the cytoplasm to the sarco/endoplasmic reticulum lumen. Sarcolipin (SLN), a transmembrane peptide, regulates the activity of SERCA1a by decreasing its Ca 2+ transport rate, but its mechanism of action is still not well understood. To decipher this mechanism, we have performed normal modes analysis in the all-atom model, with the SERCA1a-SLN complex or the isolated SERCA1a embedded in an explicit membrane. The comparison of the results allowed us to provide an explanation for the action of SLN that is in good agreement with experimental observations. In our analyses, the presence of SLN locally perturbs the TM6 transmembrane helix and as a consequence modifies the position of D800, one of the key metal-chelating residues.Additionally, it reduces the flexibility of the gating residues, V304 and E309 in TM4, at the entrance of the Ca 2+ binding sites, which would decrease the affinity for Ca 2+ . Unexpectedly, SLN has also an effect on the ATP binding site more than 35 Å away, due to the straightening of TM5, a long helix considered as the spine of the protein. The straightening of TM5 modifies the structure of the P-N linker that sits above it, and which comprises the 351 DKTG 354 conserved motif, resulting in an increase of the distance between ATP and the phosphorylation site. As a consequence, the turn-over rate could be affected. All this gives SERCA1a the propensity to go toward a Ca 2+ -deprived E2-like state in the presence of SLN and toward a Ca 2+ high-affinity E1-like state in the absence of SLN, although the SERCA1a-SLN complex was crystallized in an E1-like state. In addition to a general mechanism of inhibition of SERCA1a regulatory peptides, this study also provides an insight in the conformational transition between the E2 and E1 states. Statement of SignificanceThe role of sarco/endoplasmic reticulum calcium ATPase in muscle relaxation is essential. Impairment of its function may result in either cardiac diseases, or myopathies, and also thermogenesis defects. Inhibition of the ATPase by regulatory peptide such as sarcolipin remains unclear. The structure of the ATPase in complex with this peptide was studied by allatom normal modes analysis, an in silico technique which allows us to decipher the mechanism of inhibition of calcium transport by sarcolipin at a molecular level. Our results open the way to understanding the impact of in vivo misregulation of the ATPase activity by sarcolipin. Development of tools enhancing or preventing interaction between the ATPase and its regulatory peptide could be considered as new therapeutic approaches.During Ca 2+ transport across the sarcoplasmic reticulum membrane, SERCA1a undergoes conformational changes from the Ca 2+ high-affinity state (E1) to the Ca 2+ low-affinity state (E2). The functional cycle may be described in four main steps ( Figure 1B, adapted from Møller et al. (5)): I-SERCA1a in the presence of ATP binds two cytoplasmic Ca 2+ ions to form the E1.2Ca 2+ :ATP complex, in which the two...

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Functional and Structural Insights into Sarcolipin, a Regulator of the Sarco-Endoplasmic Reticulum Ca2+-ATPases

Cited by 10 publications

References 110 publications

Muscle Non-shivering Thermogenesis and Its Role in the Evolution of Endothermy

Muscle Non-shivering Thermogenesis and Its Role in the Evolution of Endothermy

Sarcolipin Makes Heat, but Is It Adaptive Thermogenesis?

Deciphering the mechanism of inhibition of SERCA1a by sarcolipin using molecular simulations

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