Summary: Phospholamban
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Phospholamban Edit Wikipedia article
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| Phospholamban pentamer | |||||||||
| Identifiers | |||||||||
| Symbol | Phospholamban | ||||||||
| Pfam | PF04272 | ||||||||
| InterPro | IPR005984 | ||||||||
| SCOP | 1fjk | ||||||||
| SUPERFAMILY | 1fjk | ||||||||
| TCDB | 8.A.11 | ||||||||
| OPM superfamily | 70 | ||||||||
| OPM protein | 1zll | ||||||||
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Phospholamban, also known as PLN, is a protein that in humans is encoded by the PLN gene.[1] Phospholamban is a 52-amino acid integral membrane protein that regulates the Ca2+ pump in cardiac muscle and skeletal muscle cells.[2]
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[edit] Function
The protein encoded by this gene 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 ( SERCA ) in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca++ pump leads to shorter intervals between contractions, thereby contributing to the lusitropic response elicited in heart by beta-agonists. The protein is a key regulator of cardiac diastolic function . Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure.[3]
When phospholamban is phosphorylated by PKA its ability to inhibit the sarcoplasmic reticulum calcium pump (SERCA) is lost.[4] 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 contractility and the rate of muscle relaxation , thereby decreasing stroke volume and heart rate, respectively.[5]
[edit] Clinical significance
Gene knockout of phospholamban results in animals with hyperdynamic hearts, with little apparent negative consequence.[6]
Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure .[7]
[edit] Discovery
Phospholamban was discovered by Arnold Katz and coworkers in 1974.[8]
[edit] Interactions
PLN has been shown to interact with SLN[9][10] and ATP2A1.[10][11][12]
[edit] References
- ^ 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. http://www.jbc.org/cgi/pmidlookup?view=long&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.
- ^ "Entrez Gene: PLN phospholamban". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5350.
- ^ 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. 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 10 (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. doi:10.1073/pnas.0330962100. ISSN 0027-8424. PMC 154294. PMID 12692302. //www.ncbi.nlm.nih.gov/pmc/articles/PMC154294/.
- ^ a b 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. doi:10.1073/pnas.181348298. ISSN 0027-8424. PMC 56915. PMID 11526231. //www.ncbi.nlm.nih.gov/pmc/articles/PMC56915/.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
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 [1]. Phospholamban is thought to form a pentamer in the membrane [1].
Literature references
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Smith SO, Kawakami T, Liu W, Ziliox M, Aimoto S; , J Mol Biol 2001;313:1139-1148.: Helical structure of phospholamban in membrane bilayers. PUBMED:11700069 EPMC:11700069
External database links
| PANDIT: | PF04272 |
| Pseudofam: | PF04272 |
| SCOP: | 1fjk |
| SYSTERS: | Phospholamban |
| Transporter classification: | 8.A.11 |
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].
Gene Ontology
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) |
Domain organisation
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Alignments
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| RP15 (1) |
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RP55 (4) |
RP75 (20) |
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| PP/heatmap | 1 | |||||||
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| Seed (2) |
Full (32) |
Representative proteomes | NCBI (25) |
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| RP15 (1) |
RP35 (1) |
RP55 (4) |
RP75 (20) |
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
External links
MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
HMM logo
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
Trees
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
Curation
| Seed source: | TIGRFAMs (release 2.0); |
| Previous IDs: | none |
| Type: | Domain |
| Author: | TIGRFAMs, Finn RD |
| Number in seed: | 2 |
| Number in full: | 32 |
| Average length of the domain: | 52.00 aa |
| Average identity of full alignment: | 90 % |
| Average coverage of the sequence by the domain: | 96.41 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 52 | ||||||||||||
| Family (HMM) version: | 9 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Interactions
There is 1 interaction for this family. More...
PhospholambanStructures
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 15 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 seqence.
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