1xmj
From Proteopedia
(New page: 200px<br /> <applet load="1xmj" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xmj, resolution 2.30Å" /> '''Crystal structure o...) |
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caption="1xmj, resolution 2.30Å" /> | caption="1xmj, resolution 2.30Å" /> | ||
'''Crystal structure of human deltaF508 human NBD1 domain with ATP'''<br /> | '''Crystal structure of human deltaF508 human NBD1 domain with ATP'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Cystic fibrosis is caused by defects in the cystic fibrosis transmembrane | + | Cystic fibrosis is caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR), commonly the deletion of residue Phe-508 (DeltaF508) in the first nucleotide-binding domain (NBD1), which results in a severe reduction in the population of functional channels at the epithelial cell surface. Previous studies employing incomplete NBD1 domains have attributed this to aberrant folding of DeltaF508 NBD1. We report structural and biophysical studies on complete human NBD1 domains, which fail to demonstrate significant changes of in vitro stability or folding kinetics in the presence or absence of the DeltaF508 mutation. Crystal structures show minimal changes in protein conformation but substantial changes in local surface topography at the site of the mutation, which is located in the region of NBD1 believed to interact with the first membrane spanning domain of CFTR. These results raise the possibility that the primary effect of DeltaF508 is a disruption of proper interdomain interactions at this site in CFTR rather than interference with the folding of NBD1. Interestingly, increases in the stability of NBD1 constructs are observed upon introduction of second-site mutations that suppress the trafficking defect caused by the DeltaF508 mutation, suggesting that these suppressors might function indirectly by improving the folding efficiency of NBD1 in the context of the full-length protein. The human NBD1 structures also solidify the understanding of CFTR regulation by showing that its two protein segments that can be phosphorylated both adopt multiple conformations that modulate access to the ATPase active site and functional interdomain interfaces. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1XMJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG and ATP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Channel-conductance-controlling_ATPase Channel-conductance-controlling ATPase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.3.49 3.6.3.49] Full crystallographic information is available from [http:// | + | 1XMJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=ATP:'>ATP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Channel-conductance-controlling_ATPase Channel-conductance-controlling ATPase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.3.49 3.6.3.49] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XMJ OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Emtage, S.]] | [[Category: Emtage, S.]] | ||
[[Category: GenomiX, Structural.]] | [[Category: GenomiX, Structural.]] | ||
| - | [[Category: Guggino, W | + | [[Category: Guggino, W B.]] |
| - | [[Category: Hunt, J | + | [[Category: Hunt, J F.]] |
| - | [[Category: Kearins, M | + | [[Category: Kearins, M C.]] |
| - | [[Category: Lewis, H | + | [[Category: Lewis, H A.]] |
[[Category: Lorimer, D.]] | [[Category: Lorimer, D.]] | ||
| - | [[Category: Maloney, P | + | [[Category: Maloney, P C.]] |
| - | [[Category: Noland, B | + | [[Category: Noland, B W.]] |
[[Category: Rooney, I.]] | [[Category: Rooney, I.]] | ||
| - | [[Category: Sauder, J | + | [[Category: Sauder, J M.]] |
[[Category: Wang, C.]] | [[Category: Wang, C.]] | ||
[[Category: Zhao, X.]] | [[Category: Zhao, X.]] | ||
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[[Category: cftr; nbd1 domain; deltaf508; cystic fibrosis; nucleotide-binding domain 1]] | [[Category: cftr; nbd1 domain; deltaf508; cystic fibrosis; nucleotide-binding domain 1]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:56:24 2008'' |
Revision as of 13:56, 21 February 2008
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Crystal structure of human deltaF508 human NBD1 domain with ATP
Contents |
Overview
Cystic fibrosis is caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR), commonly the deletion of residue Phe-508 (DeltaF508) in the first nucleotide-binding domain (NBD1), which results in a severe reduction in the population of functional channels at the epithelial cell surface. Previous studies employing incomplete NBD1 domains have attributed this to aberrant folding of DeltaF508 NBD1. We report structural and biophysical studies on complete human NBD1 domains, which fail to demonstrate significant changes of in vitro stability or folding kinetics in the presence or absence of the DeltaF508 mutation. Crystal structures show minimal changes in protein conformation but substantial changes in local surface topography at the site of the mutation, which is located in the region of NBD1 believed to interact with the first membrane spanning domain of CFTR. These results raise the possibility that the primary effect of DeltaF508 is a disruption of proper interdomain interactions at this site in CFTR rather than interference with the folding of NBD1. Interestingly, increases in the stability of NBD1 constructs are observed upon introduction of second-site mutations that suppress the trafficking defect caused by the DeltaF508 mutation, suggesting that these suppressors might function indirectly by improving the folding efficiency of NBD1 in the context of the full-length protein. The human NBD1 structures also solidify the understanding of CFTR regulation by showing that its two protein segments that can be phosphorylated both adopt multiple conformations that modulate access to the ATPase active site and functional interdomain interfaces.
Disease
Known diseases associated with this structure: Congenital bilateral absence of vas deferens OMIM:[602421], Cystic fibrosis OMIM:[602421], Hypertrypsinemia, neonatal OMIM:[602421], Pancreatitis, idiopathic OMIM:[602421], Sweat chloride elevation without CF OMIM:[602421]
About this Structure
1XMJ is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Channel-conductance-controlling ATPase, with EC number 3.6.3.49 Full crystallographic information is available from OCA.
Reference
Impact of the deltaF508 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure., Lewis HA, Zhao X, Wang C, Sauder JM, Rooney I, Noland BW, Lorimer D, Kearins MC, Conners K, Condon B, Maloney PC, Guggino WB, Hunt JF, Emtage S, J Biol Chem. 2005 Jan 14;280(2):1346-53. Epub 2004 Nov 3. PMID:15528182
Page seeded by OCA on Thu Feb 21 15:56:24 2008
Categories: Channel-conductance-controlling ATPase | Homo sapiens | Single protein | Condon, B. | Conners, K. | Emtage, S. | GenomiX, Structural. | Guggino, W B. | Hunt, J F. | Kearins, M C. | Lewis, H A. | Lorimer, D. | Maloney, P C. | Noland, B W. | Rooney, I. | Sauder, J M. | Wang, C. | Zhao, X. | ATP | MG | Cftr; nbd1 domain; deltaf508; cystic fibrosis; nucleotide-binding domain 1
