Molecular Events Initiating Exit of a Copper-transporting ATPase ATP7B from the Trans-Golgi Network

被引:47
作者
Hasan, Nesrin M. [2 ]
Gupta, Arnab [2 ]
Polishchuk, Elena [1 ,3 ]
Yu, Corey H. [4 ]
Polishchuk, Roman [1 ]
Dmitriev, Oleg Y. [4 ]
Lutsenko, Svetlana [2 ]
机构
[1] Telethon Inst Genet & Med, Naples, Italy
[2] Johns Hopkins Univ, Dept Physiol, Baltimore, MD 21205 USA
[3] CNR, Inst Prot Biochem, I-80131 Naples, Italy
[4] Univ Saskatchewan, Saskatoon, SK S7N 5E5, Canada
基金
美国国家卫生研究院;
关键词
WILSON-DISEASE PROTEIN; N-TERMINAL DOMAIN; MENKES DISEASE; FUNCTIONAL EXPRESSION; DEPENDENT INTERACTION; TRAFFICKING; BINDING; GENE; SIGNALS; PHOSPHORYLATION;
D O I
10.1074/jbc.M112.370403
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The copper-transporting ATPase ATP7B has a dual intracellular localization: the trans-Golgi network (TGN) and cytosolic vesicles. Changes in copper levels, kinase-mediated phosphorylation, and mutations associated with Wilson disease alter the steady-state distribution of ATP7B between these compartments. To identify a primary molecular event that triggers ATP7B exit from the TGN, we characterized the folding, activity, and trafficking of the ATP7B variants with mutations within the regulatory N-terminal domain (N-ATP7B). We found that structural changes disrupting the inter-domain contacts facilitate ATP7B exit from the TGN. Mutating Ser-340/341 in the N-ATP7B individually or together to Ala, Gly, Thr, or Asp produced active protein and shifted the steady-state localization of ATP7B to vesicles, independently of copper levels. The Ser340/341G mutant had a lower kinase-mediated phosphorylation under basal conditions and no copper-dependent phosphorylation. Thus, negative charges introduced by copper-dependent phosphorylation are not obligatory for ATP7B trafficking from the TGN. The Ser340/341A mutation did not alter the overall fold of N-ATP7B, but significantly decreased interactions with the nucleotide-binding domain, mimicking consequences of copper binding to N-ATP7B. We propose that structural changes that specifically alter the inter-domain contacts initiate exit of ATP7B from the TGN, whereas increased phosphorylation may be needed to maintain an open interface between the domains.
引用
收藏
页码:36041 / 36050
页数:10
相关论文
共 34 条
[1]   Cell-Specific Trafficking Suggests a new role for Renal ATP7B in the Intracellular Copper Storage [J].
Barnes, Natalie ;
Bartee, Mee Y. ;
Braiterman, Lita ;
Gupta, Arnab ;
Ustiyan, Vladimir ;
Zuzel, Vesna ;
Kaplan, Jack H. ;
Hubbard, Ann L. ;
Lutsenko, Svetlana .
TRAFFIC, 2009, 10 (06) :767-779
[2]   Hepatic copper-transporting ATPase ATP7B: function and inactivation at the molecular and cellular level [J].
Bartee, Mee Y. ;
Lutsenko, Svetlana .
BIOMETALS, 2007, 20 (3-4) :627-637
[3]   The Loop Connecting Metal-Binding Domains 3 and 4 of ATP7B Is a Target of a Kinase-Mediated Phosphorylation [J].
Bartee, Mee Y. ;
Ralle, Martina ;
Lutsenko, Svetlana .
BIOCHEMISTRY, 2009, 48 (24) :5573-5581
[4]   Signals for sorting of transmembrane proteins to endosomes and lysosomes [J].
Bonifacino, JS ;
Traub, LM .
ANNUAL REVIEW OF BIOCHEMISTRY, 2003, 72 :395-447
[5]   Apical targeting and Golgi retention signals reside within a 9-amino acid sequence in the copper-ATPase, ATP7B [J].
Braiterman, Lelita ;
Nyasae, Lydia ;
Guo, Yan ;
Bustos, Rodrigo ;
Lutsenko, Svetlana ;
Hubbard, Ann .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2009, 296 (02) :G433-G444
[6]   THE WILSON DISEASE GENE IS A PUTATIVE COPPER TRANSPORTING P-TYPE ATPASE SIMILAR TO THE MENKES GENE [J].
BULL, PC ;
THOMAS, GR ;
ROMMENS, JM ;
FORBES, JR ;
COX, DW .
NATURE GENETICS, 1993, 5 (04) :327-337
[7]   Intracellular trafficking of the human Wilson protein: the role of the six N-terminal metal-binding sites [J].
Cater, MA ;
Forbes, J ;
La Fontaine, S ;
Cox, D ;
Mercer, JFB .
BIOCHEMICAL JOURNAL, 2004, 380 :805-813
[8]   Copper binding to the hl-terminal metal-binding sites or the CPC motif is not essential for copper-induced trafficking of the human Wilson protein (ATP7B) [J].
Cater, Michael A. ;
La Fontaine, Sharon ;
Mercer, Julian F. B. .
BIOCHEMICAL JOURNAL, 2007, 401 :143-153
[9]   Copper-induced conformational changes in the N-terminal domain of the Wilson disease copper-transporting ATPase [J].
DiDonato, M ;
Hsu, HF ;
Narindrasorasak, S ;
Que, L ;
Sarkar, B .
BIOCHEMISTRY, 2000, 39 (07) :1890-1896
[10]   Solution structure of the N-domain of Wilson disease protein: Distinct nucleotide-binding environment and effects of disease mutations [J].
Dmitriev, O ;
Tsivkovskii, R ;
Abildgaard, F ;
Morgan, CT ;
Markley, JL ;
Lutsenko, S .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (14) :5302-5307