Document Detail

Difference in stability of the N-domain underlies distinct intracellular properties of the E1064A and H1069Q mutants of copper-transporting ATPase ATP7B.
MedLine Citation:
PMID:  21398519     Owner:  NLM     Status:  MEDLINE    
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 α1,α2-helical hairpin (α-HH) that houses Glu(1064) and His(1069) is altered. The α-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 α-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 α-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.
Oleg Y Dmitriev; Ashima Bhattacharjee; Sergiy Nokhrin; Eva-Maria E Uhlemann; Svetlana Lutsenko
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-03-11
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-02     Completed Date:  2011-07-01     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16355-62     Citation Subset:  IM    
Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
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MeSH Terms
Adenosine Triphosphatases / chemistry*,  genetics,  metabolism
Adenosine Triphosphate / chemistry*,  genetics,  metabolism
Amino Acid Substitution
Cation Transport Proteins / chemistry*,  genetics,  metabolism
HEK293 Cells
Hepatolenticular Degeneration / enzymology,  genetics
Mutation, Missense*
Protein Binding
Protein Stability
Protein Structure, Tertiary
Structure-Activity Relationship
trans-Golgi Network / enzymology,  genetics
Grant Support
P01GM067166/GM/NIGMS NIH HHS; R01 DK071865/DK/NIDDK NIH HHS; //Canadian Institutes of Health Research
Reg. No./Substance:
0/Cation Transport Proteins; 56-65-5/Adenosine Triphosphate; EC 3.6.1.-/Adenosine Triphosphatases; EC disease protein

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