2koy: Difference between revisions

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==Structure of the E1064A mutant of the N-domain of Wilson Disease Associated Protein==

== Structural highlights ==

<table><tr><td colspan='2'>[[2koy]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KOY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2KOY FirstGlance]. <br>

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== Function ==

[[http://www.uniprot.org/uniprot/ATP7B_HUMAN ATP7B_HUMAN]] Involved in the export of copper out of the cells, such as the efflux of hepatic copper into the bile.

== Publication Abstract from PubMed ==

Wilson disease (WD) is a disorder of copper metabolism caused by mutations in the Cu-transporting ATPase ATP7B. WD is characterized by significant phenotypic variability, the molecular basis of which is poorly understood. The E1064A mutation in the N-domain of ATP7B was previously shown to disrupt ATP binding. We have now determined, by NMR, the structure of the N-domain containing this mutation and compared properties of E1064A and H1069Q, another mutant with impaired ATP binding. The E1064A mutation does not change the overall fold of the N-domain. However, the position of the alpha1,alpha2-helical hairpin (alpha-HH) that houses Glu(1064) and His(1069) is altered. The alpha-HH movement produces a more open structure compared with the wild-type ATP-bound form and misaligns ATP coordinating residues, thus explaining complete loss of ATP binding. In the cell, neither the stability nor targeting of ATP7B-E1064A to the trans-Golgi network differs significantly from the wild type. This is in a contrast to the H1069Q mutation within the same alpha-HH, which greatly destabilizes protein both in vitro and in cells. The difference between two mutants can be linked to a lower stability of the alpha-HH in the H1069Q variant at the physiological temperature. We conclude that the structural stability of the N-domain rather than the loss of ATP binding plays a defining role in the ability of ATP7B to reach the trans-Golgi network, thus contributing to phenotypic variability in WD.

Difference in stability of the N-domain underlies distinct intracellular properties of the E1064A and H1069Q mutants of copper-transporting ATPase ATP7B.,Dmitriev OY, Bhattacharjee A, Nokhrin S, Uhlemann EM, Lutsenko S J Biol Chem. 2011 May 6;286(18):16355-62. Epub 2011 Mar 11. PMID:21398519<ref>PMID:21398519</ref>

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

</div>

==See Also==

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[[Category: Copper-exporting ATPase]]

[[Category: Human]]

[[Category: Large Structures]]

[[Category: Dmitriev, O Y]]

[[Category: Atp binding]]

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@@ Line 1: / Line 1: @@
 ==Structure of the E1064A mutant of the N-domain of Wilson Disease Associated Protein==
-<StructureSection load='2koy' size='340' side='right' caption='[[2koy]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='2koy' size='340' side='right'caption='[[2koy]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[2koy]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KOY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2KOY FirstGlance]. <br>
@@ Line 13: / Line 13: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/ATP7B_HUMAN ATP7B_HUMAN]] Involved in the export of copper out of the cells, such as the efflux of hepatic copper into the bile.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Wilson disease (WD) is a disorder of copper metabolism caused by mutations in the Cu-transporting ATPase ATP7B. WD is characterized by significant phenotypic variability, the molecular basis of which is poorly understood. The E1064A mutation in the N-domain of ATP7B was previously shown to disrupt ATP binding. We have now determined, by NMR, the structure of the N-domain containing this mutation and compared properties of E1064A and H1069Q, another mutant with impaired ATP binding. The E1064A mutation does not change the overall fold of the N-domain. However, the position of the alpha1,alpha2-helical hairpin (alpha-HH) that houses Glu(1064) and His(1069) is altered. The alpha-HH movement produces a more open structure compared with the wild-type ATP-bound form and misaligns ATP coordinating residues, thus explaining complete loss of ATP binding. In the cell, neither the stability nor targeting of ATP7B-E1064A to the trans-Golgi network differs significantly from the wild type. This is in a contrast to the H1069Q mutation within the same alpha-HH, which greatly destabilizes protein both in vitro and in cells. The difference between two mutants can be linked to a lower stability of the alpha-HH in the H1069Q variant at the physiological temperature. We conclude that the structural stability of the N-domain rather than the loss of ATP binding plays a defining role in the ability of ATP7B to reach the trans-Golgi network, thus contributing to phenotypic variability in WD.
+Difference in stability of the N-domain underlies distinct intracellular properties of the E1064A and H1069Q mutants of copper-transporting ATPase ATP7B.,Dmitriev OY, Bhattacharjee A, Nokhrin S, Uhlemann EM, Lutsenko S J Biol Chem. 2011 May 6;286(18):16355-62. Epub 2011 Mar 11. PMID:21398519<ref>PMID:21398519</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2koy" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 22: / Line 31: @@
 [[Category: Copper-exporting ATPase]]
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Dmitriev, O Y]]
 [[Category: Atp binding]]