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Phospholamban (PLB or PLN) pentameric Ca2+/K+ channel (Kovacs et al., 1988; Smeazzetto et al. 2013; Smeazzetto et al. 2014).  In spite of extensive experimental evidence, suggesting a pore size of 2.2 Å, the conclusion of ion channel activity for phospholamban has been questioned (Maffeo and Aksimentiev 2009).  Phosphorylation by protein kinase A and dephosphorylation by protein phosphatase 1 modulate the inhibitory activity of phospholamban (PLN), the endogenous regulator of the sarco(endo)plasmic reticulum calcium Ca2+ ATPase (SERCA). This cyclic mechanism constitutes the driving force for calcium reuptake from the cytoplasm into the myocyte lumen, regulating cardiac contractility. PLN undergoes a conformational transition between a relaxed (R) and tense (T) state, an equilibrium perturbed by the addition of SERCA. Phosphoryl transfer to Ser16 induces a conformational switch to the R state. The binding affinity of PLN to SERCA is not affected ((Kd ~ 60 μM). However, the binding surface and dynamics in domain Ib (residues 22-31) change substantially upon phosphorylation. Since PLN can be singly or doubly phosphorylated at Ser16 and Thr17, these sites may remotely control the conformation of domain Ib (Traaseth et al. 2006). Phospholamban interests with SERCA with conformational memory (Smeazzetto et al. 2017). Under physiological conditions, PLB phosphorylation induces little or no change in the interaction of the TMS with SERCA, so relief of inhibition is predominantly due to the  structural shift in the cytoplasmic domain (Martin et al. 2018). The phospholamban pentamer alters the function of the sarcoplasmic reticulum calcium pump, SERCA (Glaves et al. 2019). PLB phosphorylation serves as an allosteric molecular switch that releases inhibitory contacts and strings together the catalytic elements required for SERCA activation (Aguayo-Ortiz and Espinoza-Fonseca 2020).

Accession Number:P26678
Protein Name:PPLA aka PLB aka PLN
Molecular Weight:6109.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:1
Location1 / Topology2 / Orientation3: Mitochondrion membrane1 / Single-pass membrane protein2
Substrate calcium(2+), potassium(1+)

Cross database links:

RefSeq: NP_002658.1   
Entrez Gene ID: 5350   
Pfam: PF04272   
OMIM: 172405  gene
609909  phenotype
KEGG: hsa:5350   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0031966 C:mitochondrial membrane
GO:0016529 C:sarcoplasmic reticulum
GO:0042030 F:ATPase inhibitor activity
GO:0005246 F:calcium channel regulator activity
GO:0005515 F:protein binding
GO:0008015 P:blood circulation
GO:0006816 P:calcium ion transport
GO:0051924 P:regulation of calcium ion transport

References (9)

[1] “Structure of the rabbit phospholamban gene, cloning of the human cDNA, and assignment of the gene to human chromosome 6.”  Fujii   1828805
[2] “The human phospholamban gene: structure and expression.”  McTiernan   10198197
[3] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project   15489334
[4] “Phospholamban interacts with HAX-1, a mitochondrial protein with anti-apoptotic function.”  Vafiadaki   17241641
[5] “Solution structure of the cytoplasmic domain of phospholamban: phosphorylation leads to a local perturbation in secondary structure.”  Mortishire-Smith   7779806
[6] “Computational searching and mutagenesis suggest a structure for the pentameric transmembrane domain of phospholamban.”  Adams   7749920
[7] “Using experimental information to produce a model of the transmembrane domain of the ion channel phospholamban.”  Herzyk   9512019
[8] “Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban.”  Schmitt   12610310
[9] “A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy.”  Haghighi   16432188
1K9N   1KCH   1PLN   1PLP   1PSL   1ZLL   2HYN     

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