| First Author | Menzel J | Year | 2020 |
| Journal | Sci Signal | Volume | 13 |
| Issue | 647 | PubMed ID | 32873725 |
| Mgi Jnum | J:296128 | Mgi Id | MGI:6467713 |
| Doi | 10.1126/scisignal.aaz1436 | Citation | Menzel J, et al. (2020) 14-3-3 binding creates a memory of kinase action by stabilizing the modified state of phospholamban. Sci Signal 13(647) |
| abstractText | The cardiac membrane protein phospholamban (PLN) is targeted by protein kinase A (PKA) at Ser(16) and by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) at Thr(17) beta-Adrenergic stimulation and PKA-dependent phosphorylation of Ser(16) acutely stimulate the sarcoplasmic reticulum calcium pump (SERCA) by relieving its inhibition by PLN. CaMKII-dependent phosphorylation may lead to longer-lasting SERCA stimulation and may sustain maladaptive Ca(2+) handling. Here, we demonstrated that phosphorylation at either Ser(16) or Thr(17) converted PLN into a target for the phosphoadaptor protein 14-3-3 with different affinities. 14-3-3 proteins were localized within nanometers of PLN and endogenous 14-3-3 coimmunoprecipitated with pentameric PLN from cardiac membranes. Molecular dynamics simulations predicted different molecular contacts for peptides phosphorylated at Ser(16) or Thr(17) with the binding groove of 14-3-3, resulting in varied binding affinities. 14-3-3 binding protected either PLN phosphosite from dephosphorylation. beta-Adrenergic stimulation of isolated adult cardiomyocytes resulted in the membrane recruitment of endogenous 14-3-3. The exogenous addition of 14-3-3 to beta-adrenergic-stimulated cardiomyocytes led to prolonged SERCA activation, presumably because 14-3-3 protected PLN pentamers from dephosphorylation. Phosphorylation of Ser(16) was disrupted by the cardiomyopathy-associated Arg(14) mutation, implying that phosphorylation of Thr(17) by CaMKII may become crucial for 14-3-3 recruitment to Arg(14) PLN. Consistent with PLN acting as a dynamic hub in the control of Ca(2+) handling, our results identify 14-3-3 binding to PLN as a contractility-augmenting mechanism. |
