Chaperone-facilitated copper binding is a property common to several classes of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants
Chaperone-facilitated copper binding is a property common to several classes of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants
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DOI：
10.1073/pnas.95.11.6361
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发表时间：
1998-05-26
影响因子：
11.1
通讯作者：
Cleveland, DW
中科院分区：
文献类型：
--
作者：
Corson, LB;Strain, JJ;Cleveland, DW
Cu， Zn超氧化物歧化酶（SOD1）突变导致神经变性疾病家族性肌萎缩性侧索硬化症的毒性尚未确定（ies），对酿酒酵母中广泛的人类家族性肌萎缩性侧索硬化症相关SOD1突变体（A4V, G37R, G41D, H46R, H48Q, G85R， G93C和I113T）的分析揭示了这些突变体的一个共同特性（包括两个协调催化铜的残基）：每一种都能在体内结合铜并清除氧自由基。既不降低铜结合也不降低超氧化物清除活性是所有突变体共有的特性。所有被测试的突变体都在生理条件下结合铜，这一证明支持了SOD1突变体介导的疾病的机制，这种疾病是由铜介导的异常化学引起的，这种化学由折叠不紧密的突变酶催化（因此约束较少）。突变酶也被证明通过CCS （SOD1的特异性铜伴侣）的作用在体内获得催化铜，这反过来表明寻找这种SOD1铜伴侣的抑制剂可能代表一种治疗途径。
Mutations in Cu, Zn superoxide dismutase (SOD1) cause the neurodegenerative disease familial amyotrophic lateral sclerosis from an as-yet-unidentified toxic property(ies), Analysis in Saccharomyces cerevisiae of a broad range of human familial amyotrophic lateral sclerosis-linked SOD1 mutants (A4V, G37R, G41D, H46R, H48Q, G85R, G93C, and I113T) reveals one property common to these mutants (including two at residues that coordinate the catalytic copper): Each does indeed bind copper and scavenge oxygen-free radicals in vivo. Neither decreased copper binding nor decreased superoxide scavenging activity is a property shared by all mutants. The demonstration that shows that all mutants tested do bind copper under physiologic conditions supports a mechanism of SOD1 mutant-mediated disease arising from aberrant copper-mediated chemistry catalyzed by less tightly folded land hence less constrained) mutant enzymes. The mutant enzymes also are shown to acquire the catalytic copper in vivo through the action of CCS, a specific copper chaperone for SOD1, which in turn suggests that a search for inhibitors of this SOD1 copper chaperone may represent a therapeutic avenue.