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This is the Wikipedia entry entitled "Phospholamban". More...
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Phospholamban Edit Wikipedia article
|, CMD1P, CMH18, PLB, phospholamban|
Phospholamban, also known as PLN or PLB, is a protein that in humans is encoded by the PLN gene. Phospholamban is a 52-amino acid integral membrane protein that regulates the Calcium (Ca2+) pump in cardiac muscle cells.
This protein is found as a pentamer and is a major substrate for the cAMP-dependent protein kinase (PKA) in cardiac muscle. The protein is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca++-ATPase (SERCA2) in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The relief of inhibition on Ca++-ATPase leads to faster Ca++ uptake into the sarcoplasmic reticulum, thereby contributing to the lusitropic response elicited in heart by beta-agonists. The protein is a key regulator of . Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure.
When phospholamban is phosphorylated by its ability to inhibit the sarcoplasmic reticulum calcium pump (SERCA) is lost. Thus, activators of PKA, such as the beta-adrenergic agonist epinephrine (released by sympathetic stimulation), may enhance the rate of cardiac myocyte relaxation. In addition, since SERCA is more active, the next action potential will cause an increased release of calcium, resulting in increased contraction (positive inotropic effect). When phospholamban is not phosphorylated, such as when PKA is inactive, it can interact with and inhibit SERCA. The overall effect of phospholamban is to decrease and the rate of , thereby decreasing stroke volume and heart rate, respectively.
Gene knockout of phospholamban results in animals with hyperdynamic hearts, with little apparent negative consequence.
Mutations in this gene are a cause of inherited human dilated with refractory .
- GRCh38: Ensembl release 89: ENSG00000198523 - Ensembl, May 2017
- "Human PubMed Reference:".
- Fujii J, Zarain-Herzberg A, Willard HF, Tada M, MacLennan DH (June 1991). "Structure of the rabbit phospholamban gene, cloning of the human cDNA, and assignment of the gene to human chromosome 6". J. Biol. Chem. 266 (18): 11669–75. PMID 1828805.
- Rodriguez P, Kranias EG (December 2005). "Phospholamban: a key determinant of cardiac function and dysfunction". Arch Mal Coeur Vaiss. 98 (12): 1239–43. PMID 16435604.
- Hagemann, D; Xiao, RP (February 2002). "Dual site phospholamban phosphorylation and its physiological relevance in the heart". Trends in Cardiovascular Medicine. 12 (2): 51–6. PMID 11852250.
- "Entrez Gene: PLN phospholamban".
- Medical Physiology. Philadelphia: Saunders. 2004. ISBN 0-8089-2333-1.
- Brittsan AG, Kranias EG (December 2000). "Phospholamban and cardiac contractile function". J. Mol. Cell. Cardiol. 32 (12): 2131–9. doi:10.1006/jmcc.2000.1270. PMID 11112989.
- Luo W, Grupp IL, Harrer J, Ponniah S, Grupp G, Duffy JJ, Doetschman T, Kranias EG (September 1994). "Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation". Circ. Res. 75 (3): 401–9. doi:10.1161/01.res.75.3.401. PMID 8062415.
- Schmitt JP, Kamisago M, Asahi M, Li GH, Ahmad F, Mende U, Kranias EG, MacLennan DH, Seidman JG, Seidman CE (February 2003). "Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban". Science. 299 (5611): 1410–3. doi:10.1126/science.1081578. PMID 12610310.
- Tada M, Kirchberger MA, Repke DI, Katz AM (October 1974). "The stimulation of calcium transport in cardiac sarcoplasmic reticulum by adenosine 3':5'-monophosphate-dependent protein kinase". J Biol Chem. 249 (19): 6174–80. PMID 4371608.
- Asahi, Michio; Sugita Yuji; Kurzydlowski Kazimierz; De Leon Stella; Tada Michihiko; Toyoshima Chikashi; MacLennan David H (Apr 2003). "Sarcolipin regulates sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) by binding to transmembrane helices alone or in association with phospholamban". Proc. Natl. Acad. Sci. U.S.A. United States. 100 (9): 5040–5. Bibcode:2003PNAS..100.5040A. doi:10.1073/pnas.0330962100. ISSN 0027-8424. PMC . PMID 12692302.
- Asahi, Michio; Kurzydlowski Kazimierz; Tada Michihiko; MacLennan David H (Jul 2002). "Sarcolipin inhibits polymerization of phospholamban to induce superinhibition of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs)". J. Biol. Chem. United States. 277 (30): 26725–8. doi:10.1074/jbc.C200269200. ISSN 0021-9258. PMID 12032137.
- Asahi, M; Kimura Y; Kurzydlowski K; Tada M; MacLennan D H (Nov 1999). "Transmembrane helix M6 in sarco(endo)plasmic reticulum Ca(2+)-ATPase forms a functional interaction site with phospholamban. Evidence for physical interactions at other sites". J. Biol. Chem. UNITED STATES. 274 (46): 32855–62. doi:10.1074/jbc.274.46.32855. ISSN 0021-9258. PMID 10551848.
- Asahi, M; Green N M; Kurzydlowski K; Tada M; MacLennan D H (Aug 2001). "Phospholamban domain IB forms an interaction site with the loop between transmembrane helices M6 and M7 of sarco(endo)plasmic reticulum Ca2+ ATPases". Proc. Natl. Acad. Sci. U.S.A. United States. 98 (18): 10061–6. Bibcode:2001PNAS...9810061A. doi:10.1073/pnas.181348298. ISSN 0027-8424. PMC . PMID 11526231.
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Phospholamban Provide feedback
The regulation of calcium levels across the membrane of the sarcoplasmic reticulum involves the interplay of many membrane proteins. Phospholamban is a 52 residue integral membrane protein that is involved in reversibly inhibiting the Ca(2+) pump and regulating the flow of Ca ions across the sarcoplasmic reticulum membrane during muscle contraction and relaxation . Phospholamban is thought to form a pentamer in the membrane .
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR005984
Phospholamban (PLB) is a small protein (52 amino acids) that regulates the affinity of the cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) for calcium. PLB is present in cardiac myocytes, in slow-twitch and smooth muscle and is expressed also in aorta endothelial cells in which it could play a role in tissue relaxation. The phosphorylation/dephosphorylation of phospholamban removes and restores, respectively, its inhibitory activity on SERCA2a. It has in fact been shown that phospholamban, in its non-phosphorylated form, binds to SERCA2a and inhibits this pump by lowering its affinity for Ca2+, whereas the phosphorylated form does not exert the inhibition. PLB is phosphorylated at two sites, namely at Ser-16 for a cAMP-dependent phosphokinase and at Thr-17 for a Ca2+/calmodulin-dependent phosphokinase, phosphorylation at Ser-16 being a prerequisite for the phosphorylation at Thr-17.
The structure of a 36-amino-acid-long N-terminal fragment of human phospholamban phosphorylated at Ser-16 and Thr-17 and Cys36Ser mutated was determined from nuclear magnetic resonance data. The peptide assumes a conformation characterised by two alpha-helices connected by an irregular strand, which comprises the amino acids from Arg-13 to Pro-21. The proline is in a trans conformation. The two phosphate groups on Ser-16 and Thr-17 are shown to interact preferably with the side chains of Arg-14 and Arg-13, respectively [PUBMED:12080135].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||membrane (GO:0016020)|
|Molecular function||ATPase inhibitor activity (GO:0042030)|
|calcium channel regulator activity (GO:0005246)|
|Biological process||calcium ion transport (GO:0006816)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Seed source:||TIGRFAMs (release 2.0);|
|Author:||TIGRFAMs, Finn RD|
|Number in seed:||2|
|Number in full:||75|
|Average length of the domain:||52.00 aa|
|Average identity of full alignment:||88 %|
|Average coverage of the sequence by the domain:||89.28 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||13|
|Download:||download the raw HMM for this family|
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Phospholamban domain has been found. There are 28 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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