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5mkf

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Revision as of 21:01, 10 April 2020

cryoEM Structure of Polycystin-2 in complex with calcium and lipids

5mkf, resolution 4.20Å

Structural highlights

5mkf is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	PKD2, TRPP2 (HUMAN)
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[PKD2_HUMAN] Defects in PKD2 are the cause of polycystic kidney disease 2 (PKD2) [MIM:613095]. PKD2 is a disorder characterized by progressive formation and enlargement of cysts in both kidneys, typically leading to end-stage renal disease in adult life. Cysts also occurs in the liver and other organs. It represents approximately 15% of the cases of autosomal dominant polycystic kidney disease. PKD2 is clinically milder than PKD1 but it has a deleterious impact on overall life expectancy.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

Function

[PKD2_HUMAN] Involved in fluid-flow mechanosensation by the primary cilium in renal epithelium (By similarity). PKD1 and PKD2 may function through a common signaling pathway that is necessary for normal tubulogenesis (By similarity). Acts as a regulator of cilium length, together with PKD1 (By similarity). The dynamic control of cilium length is essential in the regulation of mechanotransductive signaling. The cilium length response creates a negative feedback loop whereby fluid shear-mediated deflection of the primary cilium, which decreases intracellular cAMP, leads to cilium shortening and thus decreases flow-induced signaling (By similarity). Functions as a calcium permeable cation channel.

Publication Abstract from PubMed

Polycystin-2 (PC2), a calcium-activated cation TRP channel, is involved in diverse Ca2+ signaling pathways. Malfunctioning Ca2+ regulation in PC2 causes autosomal-dominant polycystic kidney disease. Here we report two cryo-EM structures of distinct channel states of full-length human PC2 in complex with lipids and cations. The structures reveal conformational differences in the selectivity filter and in the large exoplasmic domain (TOP domain), which displays differing N-glycosylation. The more open structure has one cation bound below the selectivity filter (single-ion mode, PC2SI), whereas multiple cations are bound along the translocation pathway in the second structure (multi-ion mode, PC2MI). Ca2+ binding at the entrance of the selectivity filter suggests Ca2+ blockage in PC2MI, and we observed density for the Ca2+-sensing C-terminal EF hand in the unblocked PC2SI state. The states show altered interactions of lipids with the pore loop and TOP domain, thus reflecting the functional diversity of PC2 at different locations, owing to different membrane compositions.

Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2.,Wilkes M, Madej MG, Kreuter L, Rhinow D, Heinz V, De Sanctis S, Ruppel S, Richter RM, Joos F, Grieben M, Pike AC, Huiskonen JT, Carpenter EP, Kuhlbrandt W, Witzgall R, Ziegler C Nat Struct Mol Biol. 2017 Jan 16. doi: 10.1038/nsmb.3357. PMID:28092368^[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Veldhuisen B, Saris JJ, de Haij S, Hayashi T, Reynolds DM, Mochizuki T, Elles R, Fossdal R, Bogdanova N, van Dijk MA, Coto E, Ravine D, Norby S, Verellen-Dumoulin C, Breuning MH, Somlo S, Peters DJ. A spectrum of mutations in the second gene for autosomal dominant polycystic kidney disease (PKD2). Am J Hum Genet. 1997 Sep;61(3):547-55. PMID:9326320
↑ Reynolds DM, Hayashi T, Cai Y, Veldhuisen B, Watnick TJ, Lens XM, Mochizuki T, Qian F, Maeda Y, Li L, Fossdal R, Coto E, Wu G, Breuning MH, Germino GG, Peters DJ, Somlo S. Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease. J Am Soc Nephrol. 1999 Nov;10(11):2342-51. PMID:10541293
↑ Torra R, Viribay M, Telleria D, Badenas C, Watson M, Harris P, Darnell A, San Millan JL. Seven novel mutations of the PKD2 gene in families with autosomal dominant polycystic kidney disease. Kidney Int. 1999 Jul;56(1):28-33. PMID:10411676 doi:kid534
↑ Watnick T, He N, Wang K, Liang Y, Parfrey P, Hefferton D, St George-Hyslop P, Germino G, Pei Y. Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations. Nat Genet. 2000 Jun;25(2):143-4. PMID:10835625 doi:10.1038/75981
↑ Reiterova J, Stekrova J, Peters DJ, Kapras J, Kohoutova M, Merta M, Zidovska J. Four novel mutations of the PKD2 gene in Czech families with autosomal dominant polycystic kidney disease. Hum Mutat. 2002 May;19(5):573. PMID:11968093 doi:10.1002/humu.9035
↑ Magistroni R, He N, Wang K, Andrew R, Johnson A, Gabow P, Dicks E, Parfrey P, Torra R, San-Millan JL, Coto E, Van Dijk M, Breuning M, Peters D, Bogdanova N, Ligabue G, Albertazzi A, Hateboer N, Demetriou K, Pierides A, Deltas C, St George-Hyslop P, Ravine D, Pei Y. Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2003 May;14(5):1164-74. PMID:12707387
↑ Stekrova J, Reiterova J, Merta M, Damborsky J, Zidovska J, Kebrdlova V, Kohoutova M. PKD2 mutations in a Czech population with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2004 May;19(5):1116-22. Epub 2004 Feb 19. PMID:14993477 doi:10.1093/ndt/gfh083
↑ Peltola P, Lumiaho A, Miettinen R, Pihlajamaki J, Sandford R, Laakso M. Genetics and phenotypic characteristics of autosomal dominant polycystic kidney disease in Finns. J Mol Med (Berl). 2005 Aug;83(8):638-46. Epub 2005 Mar 17. PMID:15772804 doi:10.1007/s00109-005-0644-6
↑ Hoefele J, Mayer K, Scholz M, Klein HG. Novel PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant. 2011 Jul;26(7):2181-8. doi: 10.1093/ndt/gfq720. Epub, 2010 Nov 29. PMID:21115670 doi:10.1093/ndt/gfq720
↑ Wilkes M, Madej MG, Kreuter L, Rhinow D, Heinz V, De Sanctis S, Ruppel S, Richter RM, Joos F, Grieben M, Pike AC, Huiskonen JT, Carpenter EP, Kuhlbrandt W, Witzgall R, Ziegler C. Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2. Nat Struct Mol Biol. 2017 Jan 16. doi: 10.1038/nsmb.3357. PMID:28092368 doi:http://dx.doi.org/10.1038/nsmb.3357

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5mkf"

@@ Line 3: / Line 3: @@
 <SX load='5mkf' size='340' side='right' viewer='molstar' caption='[[5mkf]], [[Resolution|resolution]] 4.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5mkf]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MKF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MKF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5mkf]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MKF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MKF FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CHS:4-AMINO-5-CYCLOHEXYL-3-HYDROXY-PENTANOIC+ACID'>CHS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene>, <scene name='pdbligand=PX6:1,2-DIPALMITOYL-SN-GLYCERO-3-PHOSPHATE'>PX6</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CHS:4-AMINO-5-CYCLOHEXYL-3-HYDROXY-PENTANOIC+ACID'>CHS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene>, <scene name='pdbligand=PX6:1,2-DIPALMITOYL-SN-GLYCERO-3-PHOSPHATE'>PX6</scene></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PKD2, TRPP2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5mkf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mkf OCA], [http://pdbe.org/5mkf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mkf RCSB], [http://www.ebi.ac.uk/pdbsum/5mkf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mkf ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5mkf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mkf OCA], [http://pdbe.org/5mkf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mkf RCSB], [http://www.ebi.ac.uk/pdbsum/5mkf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mkf ProSAT]</span></td></tr>
 </table>
 == Disease ==

5mkf

From Proteopedia

Revision as of 21:01, 10 April 2020

cryoEM Structure of Polycystin-2 in complex with calcium and lipids

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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