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| | ==The second Ca2+-binding domain of the Na+-Ca2+ exchanger is essential for regulation: crystal structures and mutational analysis== | | ==The second Ca2+-binding domain of the Na+-Ca2+ exchanger is essential for regulation: crystal structures and mutational analysis== |
| - | <StructureSection load='2qvm' size='340' side='right' caption='[[2qvm]], [[Resolution|resolution]] 1.70Å' scene=''> | + | <StructureSection load='2qvm' size='340' side='right'caption='[[2qvm]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2qvm]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Canlf Canlf]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QVM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2QVM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2qvm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Canis_lupus_familiaris Canis lupus familiaris]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QVM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QVM 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></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]] 1.703Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2dpk|2dpk]], [[2fwu|2fwu]], [[2qvk|2qvk]]</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></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SLC8A1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9615 CANLF])</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=2qvm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qvm OCA], [https://pdbe.org/2qvm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qvm RCSB], [https://www.ebi.ac.uk/pdbsum/2qvm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qvm 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=2qvm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qvm OCA], [http://pdbe.org/2qvm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2qvm RCSB], [http://www.ebi.ac.uk/pdbsum/2qvm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2qvm ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NAC1_CANFA NAC1_CANFA]] Rapidly transports Ca(2+) during excitation-contraction coupling. Ca(2+) is extruded from the cell during relaxation so as to prevent overloading of intracellular stores. | + | [https://www.uniprot.org/uniprot/NAC1_CANLF NAC1_CANLF] Mediates the exchange of one Ca(2+) ion against three to four Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes (PubMed:1700476, PubMed:1785844, PubMed:9486131, PubMed:17962412). Contributes to Ca(2+) transport during excitation-contraction coupling in muscle. In a first phase, voltage-gated channels mediate the rapid increase of cytoplasmic Ca(2+) levels due to release of Ca(2+) stores from the endoplasmic reticulum. SLC8A1 mediates the export of Ca(2+) from the cell during the next phase, so that cytoplasmic Ca(2+) levels rapidly return to baseline. Required for normal embryonic heart development and the onset of heart contractions (By similarity).[UniProtKB:P70414]<ref>PMID:1700476</ref> <ref>PMID:1785844</ref> <ref>PMID:17962412</ref> <ref>PMID:19332552</ref> <ref>PMID:9486131</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Canlf]] | + | [[Category: Canis lupus familiaris]] |
| - | [[Category: Abramson, J]] | + | [[Category: Large Structures]] |
| - | [[Category: Besserer, G Mercado]] | + | [[Category: Abramson J]] |
| - | [[Category: Cascio, D]] | + | [[Category: Cascio D]] |
| - | [[Category: Chaptal, V]] | + | [[Category: Chaptal V]] |
| - | [[Category: Calcium binding domain]] | + | [[Category: Mercado Besserer G]] |
| - | [[Category: Calcium regulation]]
| + | |
| - | [[Category: Cbd2]]
| + | |
| - | [[Category: Metal binding protein]]
| + | |
| - | [[Category: Ncx]]
| + | |
| Structural highlights
Function
NAC1_CANLF Mediates the exchange of one Ca(2+) ion against three to four Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes (PubMed:1700476, PubMed:1785844, PubMed:9486131, PubMed:17962412). Contributes to Ca(2+) transport during excitation-contraction coupling in muscle. In a first phase, voltage-gated channels mediate the rapid increase of cytoplasmic Ca(2+) levels due to release of Ca(2+) stores from the endoplasmic reticulum. SLC8A1 mediates the export of Ca(2+) from the cell during the next phase, so that cytoplasmic Ca(2+) levels rapidly return to baseline. Required for normal embryonic heart development and the onset of heart contractions (By similarity).[UniProtKB:P70414][1] [2] [3] [4] [5]
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 Na(+)-Ca(2+) exchanger plays a central role in cardiac contractility by maintaining Ca(2+) homeostasis. Two Ca(2+)-binding domains, CBD1 and CBD2, located in a large intracellular loop, regulate activity of the exchanger. Ca(2+) binding to these regulatory domains activates the transport of Ca(2+) across the plasma membrane. Previously, we solved the structure of CBD1, revealing four Ca(2+) ions arranged in a tight planar cluster. Here, we present structures of CBD2 in the Ca(2+)-bound (1.7-A resolution) and -free (1.4-A resolution) conformations. Like CBD1, CBD2 has a classical Ig fold but coordinates only two Ca(2+) ions in primary and secondary Ca(2+) sites. In the absence of Ca(2+), Lys(585) stabilizes the structure by coordinating two acidic residues (Asp(552) and Glu(648)), one from each of the Ca(2+)-binding sites, and prevents a substantial protein unfolding. We have mutated all of the acidic residues that coordinate the Ca(2+) ions and have examined the effects of these mutations on regulation of exchange activity. Three mutations (E516L, D578V, and E648L) at the primary Ca(2+) site completely remove Ca(2+) regulation, placing the exchanger into a constitutively active state. These are the first data defining the role of CBD2 as a regulatory domain in the Na(+)-Ca(2+) exchanger.
The second Ca2+-binding domain of the Na+ Ca2+ exchanger is essential for regulation: crystal structures and mutational analysis.,Besserer GM, Ottolia M, Nicoll DA, Chaptal V, Cascio D, Philipson KD, Abramson J Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18467-72. Epub 2007 Oct 25. PMID:17962412[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nicoll DA, Longoni S, Philipson KD. Molecular cloning and functional expression of the cardiac sarcolemmal Na(+)-Ca2+ exchanger. Science. 1990 Oct 26;250(4980):562-5. PMID:1700476
- ↑ Nicoll DA, Philipson KD. Molecular studies of the cardiac sarcolemmal sodium-calcium exchanger. Ann N Y Acad Sci. 1991;639:181-8. PMID:1785844
- ↑ Besserer GM, Ottolia M, Nicoll DA, Chaptal V, Cascio D, Philipson KD, Abramson J. The second Ca2+-binding domain of the Na+ Ca2+ exchanger is essential for regulation: crystal structures and mutational analysis. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18467-72. Epub 2007 Oct 25. PMID:17962412
- ↑ Chaptal V, Ottolia M, Mercado-Besserer G, Nicoll DA, Philipson KD, Abramson J. Structure and functional analysis of a Ca2+ sensor mutant of the Na+/Ca2+ exchanger. J Biol Chem. 2009 May 29;284(22):14688-92. Epub 2009 Mar 30. PMID:19332552 doi:10.1074/jbc.C900037200
- ↑ Linck B, Qiu Z, He Z, Tong Q, Hilgemann DW, Philipson KD. Functional comparison of the three isoforms of the Na+/Ca2+ exchanger (NCX1, NCX2, NCX3). Am J Physiol. 1998 Feb;274(2 Pt 1):C415-23. PMID:9486131
- ↑ Besserer GM, Ottolia M, Nicoll DA, Chaptal V, Cascio D, Philipson KD, Abramson J. The second Ca2+-binding domain of the Na+ Ca2+ exchanger is essential for regulation: crystal structures and mutational analysis. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18467-72. Epub 2007 Oct 25. PMID:17962412
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