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6d1w

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human PKD2 F604P mutant

6d1w, resolution 3.54Å

Structural highlights

6d1w 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

PKD2 and PKD1 genes are mutated in human autosomal dominant polycystic kidney disease. PKD2 can form either a homomeric cation channel or a heteromeric complex with the PKD1 receptor, presumed to respond to ligand(s) and/or mechanical stimuli. Here, we identify a two-residue hydrophobic gate in PKD2L1, and a single-residue hydrophobic gate in PKD2. We find that a PKD2 gain-of-function gate mutant effectively rescues PKD2 knockdown-induced phenotypes in embryonic zebrafish. The structure of a PKD2 activating mutant F604P by cryo-electron microscopy reveals a pi- to alpha-helix transition within the pore-lining helix S6 that leads to repositioning of the gate residue and channel activation. Overall the results identify hydrophobic gates and a gating mechanism of PKD2 and PKD2L1.

Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels.,Zheng W, Yang X, Hu R, Cai R, Hofmann L, Wang Z, Hu Q, Liu X, Bulkey D, Yu Y, Tang J, Flockerzi V, Cao Y, Cao E, Chen XZ Nat Commun. 2018 Jun 13;9(1):2302. doi: 10.1038/s41467-018-04586-x. PMID:29899465^[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
↑ Zheng W, Yang X, Hu R, Cai R, Hofmann L, Wang Z, Hu Q, Liu X, Bulkey D, Yu Y, Tang J, Flockerzi V, Cao Y, Cao E, Chen XZ. Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels. Nat Commun. 2018 Jun 13;9(1):2302. doi: 10.1038/s41467-018-04586-x. PMID:29899465 doi:http://dx.doi.org/10.1038/s41467-018-04586-x

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/6d1w"

@@ Line 1: / Line 1: @@
 ==human PKD2 F604P mutant==
-<StructureSection load='6d1w' size='340' side='right' caption='[[6d1w]], [[Resolution|resolution]] 3.54&Aring;' scene=''>
+<SX load='6d1w' size='340' side='right' viewer='molstar' caption='[[6d1w]], [[Resolution|resolution]] 3.54&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6d1w]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D1W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D1W FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6d1w]] 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=6D1W OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6D1W FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=6d1w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d1w OCA], [http://pdbe.org/6d1w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d1w RCSB], [http://www.ebi.ac.uk/pdbsum/6d1w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d1w ProSAT]</span></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://proteopedia.org/fgij/fg.htm?mol=6d1w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d1w OCA], [http://pdbe.org/6d1w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d1w RCSB], [http://www.ebi.ac.uk/pdbsum/6d1w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d1w ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 23: / Line 24: @@
 <references/>
 __TOC__
-</StructureSection>
+</SX>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Bulkley, D]]
 [[Category: Cao, E]]

6d1w

From Proteopedia

Current revision

human PKD2 F604P mutant

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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