165 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 depolymerization of the PLN pentamer would be necessary to activate the inhibitory function of the PLN monomers.137,138 Interestingly, PLN pentamers are found next to SERCA2a, and PKA preferentially phosphorylates PLN pentamers. This suggests a model in which PLN pentamers not only delay the phosphorylation of PLN monomeric but also indirectly regulate SERCA by prolonging SERCA-PLN interaction, thus revealing an additional role for PLN pentamers in the regulatory process.139 Moreover, the deletion of amino acid 14 in PLN has been shown to partially destabilize the PLN pentamer, potentially increasing the concentration of PLN monomer.140 However, a recent preprint study described the hyper-stabilization of PLNR14del pentamers which leads to a decrease in the population of PLN monomers available to inhibit SERCA.101 This enhanced pentamer stability and impaired PLN binding dynamics could potentially lead to a decreased binding of R14del-PLN to SERCA, which contradicts the previous observation. Moreover, a mathematical model of the PLN-R14del regulatory network suggests that this mutation could impair molecular noise filtering in the β-adrenergic signaling network. In this study, simulations show that phosphorylation delay and bistability, due to cooperative dephosphorylation of pentamers, act as complementary filters that reduce the effect of random fluctuations in PKA activity, thereby ensuring consistent monomer phosphorylation and SERCA activity despite noisy upstream signals. This suggests that molecular noise filtering in the β-adrenergic signaling network may be important in preventing cardiac arrhythmias.141 Further studies will be needed to confirm these findings and determine the precise mechanisms by which molecular noise filtering in the β-adrenergic signaling network is disrupted by the PLNR14del mutation. Nevertheless, the study highlights the potential importance of understanding the regulatory networks underlying cardiac function and the potential impact of genetic mutations on these networks. PLN binding partners In addition to its canonical interaction with SERCA2a, PLN forms a multimeric complex interacting, directly and indirectly, with several partners including Protein Phosphatase I (PP1), inhibitor-1 (I-1), the anti-apoptotic HS-1 associated protein X-1 (HAX-1), and the small Heat shock protein 20 (Hsp20)142,143, which regulate SR calcium-cycling and contractility. Thus, the PLN-R14del mutation could affect PLN binding partners and lead to aberrant calcium handling, arrhythmia, and cellular damage.144 Indeed, a recent study revealed alterations in PLN-R14del interactions to multiple known binding partners (SERCA2a, HAX-1, PP1 Regulatory Subunit 3A and histidine-rich calcium-binding protein, HRC) causing inhibition of SERCA2a activity, and leading to impaired SR Ca2+ cycling and depressed cardiac function.145 Interestingly, a new PLN-binding protein has been identified in mouse ventricular tissue.146 This study demonstrated that phosphorylation at either Ser16 or Thr17 converted PLN into a target for the phospho-adaptor protein 14-3-3 with different affinities. 14-3-3 protein protected PLN phosphorylation sites from dephosphorylation and the exogenous addition
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