Molecular mechanism of copper transport in Wilson disease.
Molecular mechanism of copper transport in Wilson disease.
复制标题
威尔逊病中铜转运的分子机制。
DOI：
10.1289/ehp.02110s5695
复制
发表时间：
2002-10
影响因子：
10.4
通讯作者：
Sarkar, B
中科院分区：
文献类型：
--
作者：
Fatemi, N;Sarkar, B
关键词：
肝豆状核变性是一种常染色体隐性铜代谢紊乱病。肝豆状核变性蛋白是一种可能的铜转运P型ATP7B酶，其功能障碍会导致铜在肝脏和大脑中的毒性积聚，导致肝脏和/或神经系统的症状。该ATPase的胞质N末端结构域(约70 kDa)由6个重金属结合结构域组成，每个结构域都含有保守的金属结合基序GMTCXXC。N-末端结构域(Wilson病铜结合结构域[WCBD])已被表达、纯化，并利用各种技术进行了鉴定。WCBD竞争性地结合了+1氧化态的六个铜原子，并且比所有其他金属具有更大的亲和力。铜原子被两个半胱氨酸以扭曲的线性几何构型配位。铜以协同的方式与WCBD结合，并引起二级和三级构象变化。锌与WCBD的结合也用圆二色谱进行了表征，结果表明，锌与WCBD的结合产生了与铜完全不同的构象变化。ATP7B的磷酸化/核苷酸结合区也已被表达和鉴定，并表明能够与ATP结合，但缺乏ATPase活性。与ATP7B的第六跨膜结构域相对应的多肽已经被构建，并被证明在与单个铜原子结合时经历了二次构象变化。最后，构建了一个由WCBD和缺失N-末端结构域的锌转运ATPase截短的ZntA组成的嵌合蛋白，并对其金属离子选择性进行了分析。这些结果表明，核心决定了P型ATPase的金属离子专一性，N-末端的金属结合域可能起着调节作用。
Wilson disease is an autosomal recessive disorder of copper metabolism. The Wilson disease protein is a putative copper-transporting P-type ATPase, ATP7B, whose malfunction results in the toxic accumulation of copper in the liver and brain, causing the hepatic and/or neurological symptoms accompanying this disease. The cytosolic N-terminal domain (approximately 70 kDa) of this ATPase comprises six heavy metal-associated domains, each of which contains the conserved metal-binding motif GMTCXXC. The N-terminal domain (Wilson disease copper-binding domain [WCBD]) has been expressed, purified, and characterized using various techniques. The WCBD binds six atoms of copper in the +1 oxidation state competitively, and with a greater affinity than all other metals. The copper atom is coordinated by two cysteines in a distorted linear geometry. Copper binds the WCBD in a cooperative manner and induces secondary and tertiary conformation changes. Zinc binding to the WCBD has also been characterized by circular dichroism spectroscopy and shown to produce conformational changes that are completely different from those induced by copper. The phosphorylation/nucleotide-binding domain of ATP7B has also been expressed and characterized and shown to be capable of binding ATP but lacking ATPase activity. A peptide corresponding to the sixth transmembrane domain of ATP7B has been constructed and shown to undergo secondary conformational changes upon binding a single atom of copper. Finally, a chimeric protein consisting of the WCBD and truncated ZntA, a zinc-transporting ATPase lacking the N-terminal domain, has been constructed and analyzed for metal ion selectivity. These results suggest that the core determines the metal ion specificity of P-type ATPases, and the N-terminal metal-binding domain may play a regulatory role.
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影响因子：
30.8
作者：
BULL, PC;THOMAS, GR;COX, DW
通讯作者：
COX, DW
影响因子：
39.2
作者：
BREWER, GJ;HILL, GM;RABBANI, P
通讯作者：
RABBANI, P
影响因子：
2.9
作者：
DiDonato, M;Hsu, HF;Sarkar, B
通讯作者：
Sarkar, B
影响因子：
4.8
作者：
Hung, IH;Suzuki, M;Gitlin, JD
通讯作者：
Gitlin, JD
影响因子：
30.8
作者：
MERCER, JFB;LIVINGSTON, J;GLOVER, TW
通讯作者：
GLOVER, TW