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| | ==STRUCTURAL BASIS OF THE NHERF PDZ1-CFTR INTERACTION== | | ==STRUCTURAL BASIS OF THE NHERF PDZ1-CFTR INTERACTION== |
| - | <StructureSection load='1i92' size='340' side='right' caption='[[1i92]], [[Resolution|resolution]] 1.70Å' scene=''> | + | <StructureSection load='1i92' size='340' side='right'caption='[[1i92]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1i92]] is a 1 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=1I92 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1I92 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1i92]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1I92 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1I92 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1g9o|1g9o]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NHERF ([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'>[https://proteopedia.org/fgij/fg.htm?mol=1i92 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1i92 OCA], [https://pdbe.org/1i92 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1i92 RCSB], [https://www.ebi.ac.uk/pdbsum/1i92 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1i92 ProSAT]</span></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=1i92 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1i92 OCA], [http://pdbe.org/1i92 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1i92 RCSB], [http://www.ebi.ac.uk/pdbsum/1i92 PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/NHRF1_HUMAN NHRF1_HUMAN]] Defects in SLC9A3R1 are the cause of hypophosphatemic nephrolithiasis/osteoporosis type 2 (NPHLOP2) [MIM:[http://omim.org/entry/612287 612287]]. Hypophosphatemia results from idiopathic renal phosphate loss. It contributes to the pathogenesis of hypophosphatemic urolithiasis (formation of urinary calculi) as well to that of hypophosphatemic osteoporosis (bone demineralization).<ref>PMID:18784102</ref> <ref>PMID:22506049</ref> | + | [https://www.uniprot.org/uniprot/NHRF1_HUMAN NHRF1_HUMAN] Defects in SLC9A3R1 are the cause of hypophosphatemic nephrolithiasis/osteoporosis type 2 (NPHLOP2) [MIM:[https://omim.org/entry/612287 612287]. Hypophosphatemia results from idiopathic renal phosphate loss. It contributes to the pathogenesis of hypophosphatemic urolithiasis (formation of urinary calculi) as well to that of hypophosphatemic osteoporosis (bone demineralization).<ref>PMID:18784102</ref> <ref>PMID:22506049</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NHRF1_HUMAN NHRF1_HUMAN]] Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for recycling of internalized ADRB2. Was first known to play a role in the regulation of the activity and subcellular location of SLC9A3. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May enhance Wnt signaling. May participate in HTR4 targeting to microvilli (By similarity). Involved in the regulation of phosphate reabsorption in the renal proximal tubules.<ref>PMID:9430655</ref> <ref>PMID:9096337</ref> <ref>PMID:10499588</ref> <ref>PMID:18784102</ref> | + | [https://www.uniprot.org/uniprot/NHRF1_HUMAN NHRF1_HUMAN] Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for recycling of internalized ADRB2. Was first known to play a role in the regulation of the activity and subcellular location of SLC9A3. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May enhance Wnt signaling. May participate in HTR4 targeting to microvilli (By similarity). Involved in the regulation of phosphate reabsorption in the renal proximal tubules.<ref>PMID:9430655</ref> <ref>PMID:9096337</ref> <ref>PMID:10499588</ref> <ref>PMID:18784102</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i9/1i92_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i9/1i92_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
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| | </div> | | </div> |
| | <div class="pdbe-citations 1i92" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 1i92" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Sodium-hydrogen exchange regulatory factor|Sodium-hydrogen exchange regulatory factor]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Karthikeyan, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Ladias, J A.A]] | + | [[Category: Karthikeyan S]] |
| - | [[Category: Leung, T]] | + | [[Category: Ladias JAA]] |
| - | [[Category: Cftr]] | + | [[Category: Leung T]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Nherf]]
| + | |
| - | [[Category: Pdz]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Disease
NHRF1_HUMAN Defects in SLC9A3R1 are the cause of hypophosphatemic nephrolithiasis/osteoporosis type 2 (NPHLOP2) [MIM:612287. Hypophosphatemia results from idiopathic renal phosphate loss. It contributes to the pathogenesis of hypophosphatemic urolithiasis (formation of urinary calculi) as well to that of hypophosphatemic osteoporosis (bone demineralization).[1] [2]
Function
NHRF1_HUMAN Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for recycling of internalized ADRB2. Was first known to play a role in the regulation of the activity and subcellular location of SLC9A3. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May enhance Wnt signaling. May participate in HTR4 targeting to microvilli (By similarity). Involved in the regulation of phosphate reabsorption in the renal proximal tubules.[3] [4] [5] [6]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The PDZ1 domain of the Na(+)/H(+) exchanger regulatory factor (NHERF) binds with nanomolar affinity to the carboxyl-terminal sequence QDTRL of the cystic fibrosis transmembrane conductance regulator (CFTR) and plays a central role in the cellular localization and physiological regulation of this chloride channel. The crystal structure of human NHERF PDZ1 bound to the carboxyl-terminal peptide QDTRL has been determined at 1.7-A resolution. The structure reveals the specificity and affinity determinants of the PDZ1-CFTR interaction and provides insights into carboxyl-terminal leucine recognition by class I PDZ domains. The peptide ligand inserts into the PDZ1 binding pocket forming an additional antiparallel beta-strand to the PDZ1 beta-sheet, and an extensive network of hydrogen bonds and hydrophobic interactions stabilize the complex. Remarkably, the guanido group of arginine at position -1 of the CFTR peptide forms two salt bridges and two hydrogen bonds with PDZ1 residues Glu(43) and Asn(22), respectively, providing the structural basis for the contribution of the penultimate amino acid of the peptide ligand to the affinity of the interaction.
Structural basis of the Na+/H+ exchanger regulatory factor PDZ1 interaction with the carboxyl-terminal region of the cystic fibrosis transmembrane conductance regulator.,Karthikeyan S, Leung T, Ladias JA J Biol Chem. 2001 Jun 8;276(23):19683-6. Epub 2001 Apr 13. PMID:11304524[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Karim Z, Gerard B, Bakouh N, Alili R, Leroy C, Beck L, Silve C, Planelles G, Urena-Torres P, Grandchamp B, Friedlander G, Prie D. NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med. 2008 Sep 11;359(11):1128-35. PMID:18784102 doi:359/11/1128
- ↑ Courbebaisse M, Leroy C, Bakouh N, Salaun C, Beck L, Grandchamp B, Planelles G, Hall RA, Friedlander G, Prie D. A new human NHERF1 mutation decreases renal phosphate transporter NPT2a expression by a PTH-independent mechanism. PLoS One. 2012;7(4):e34764. doi: 10.1371/journal.pone.0034764. Epub 2012 Apr 10. PMID:22506049 doi:10.1371/journal.pone.0034764
- ↑ Murthy A, Gonzalez-Agosti C, Cordero E, Pinney D, Candia C, Solomon F, Gusella J, Ramesh V. NHE-RF, a regulatory cofactor for Na(+)-H+ exchange, is a common interactor for merlin and ERM (MERM) proteins. J Biol Chem. 1998 Jan 16;273(3):1273-6. PMID:9430655
- ↑ Yun CH, Oh S, Zizak M, Steplock D, Tsao S, Tse CM, Weinman EJ, Donowitz M. cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3010-5. PMID:9096337
- ↑ Cao TT, Deacon HW, Reczek D, Bretscher A, von Zastrow M. A kinase-regulated PDZ-domain interaction controls endocytic sorting of the beta2-adrenergic receptor. Nature. 1999 Sep 16;401(6750):286-90. PMID:10499588 doi:10.1038/45816
- ↑ Karim Z, Gerard B, Bakouh N, Alili R, Leroy C, Beck L, Silve C, Planelles G, Urena-Torres P, Grandchamp B, Friedlander G, Prie D. NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med. 2008 Sep 11;359(11):1128-35. PMID:18784102 doi:359/11/1128
- ↑ Karthikeyan S, Leung T, Ladias JA. Structural basis of the Na+/H+ exchanger regulatory factor PDZ1 interaction with the carboxyl-terminal region of the cystic fibrosis transmembrane conductance regulator. J Biol Chem. 2001 Jun 8;276(23):19683-6. Epub 2001 Apr 13. PMID:11304524 doi:10.1074/jbc.C100154200
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