The regulatory mechanism of the caspase 6 pro-domain revealed by crystal structure and biochemical assays

CaoQ.; WangX.-J.; LiL.-F.SuX.-D.

首页> 外文期刊>Acta crystallographica.Section D Biological crystallography. >The regulatory mechanism of the caspase 6 pro-domain revealed by crystal structure and biochemical assays

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The regulatory mechanism of the caspase 6 pro-domain revealed by crystal structure and biochemical assays

机译：半胱天冬酶的调控机制6晶体结构和pro-domain透露生化检测

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Caspase 6 (CASP6) is a neuron degeneration-related protease and is widely considered to be a potential drug-design target against neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. The N-terminal pro-peptide of CASP6, also referred to as the pro-domain, contains 23 residues and its functional role remains elusive. In this study, the crystal structure of a full-length CASP6 zymogen mutant, proCASP6H121A, was solved. Although the pro-domain was flexible in the crystal, without visible electron density, structural analyses combined with biochemical assays revealed that the pro-domain inhibited CASP6 auto-activation by inhibiting intramolecular cleavage at the intersubunit cleavage site TEVD193 and also by preventing this site from intermolecular cleavage at low protein concentration through a so-called 'suicide-protection' mechanism. Further experiments showed that the length of the pro-domain and the side chain of Asn18 played critical roles in suicide protection. These results disclosed a new inhibitory mechanism of CASP6 and shed light on the pathogenesis and therapeutically relevant study of CASP6-related neurodegenerative diseases.

机译：半胱天冬酶6 (CASP6)是一个神经元degeneration-related蛋白酶,被广泛认为是一个潜在的药物设计目标对神经退行性疾病,如亨廷顿氏舞蹈症疾病和阿尔茨海默氏症。pro-peptide CASP6,也称为pro-domain,包含23残留及其功能作用仍然是难以捉摸的。一个长篇CASP6的晶体结构proCASP6H121A发酵菌突变体,是解决。虽然pro-domain是灵活的水晶,没有可见的电子密度,结构分析与生化相结合化验显示,pro-domain抑制CASP6自动激活通过抑制分子内intersubunit乳沟裂解位点TEVD193也通过防止这一点网站从低蛋白分子间乳沟集中在一个所谓的“suicide-protection”机制。实验显示的长度pro-domain Asn18的侧链自杀式保护的关键角色。结果披露新的抑制机制CASP6阐明发病机理和CASP6-related的治疗相关的研究神经退行性疾病。

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《Acta crystallographica.Section D Biological crystallography.》 |2014年第1期|58-67|共10页
作者
CaoQ.; WangX.-J.; LiL.-F.SuX.-D.;
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作者单位

State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University;

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正文语种英语
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关键词
crystal structure; CASP6 gene; Huntington DiseaseNeurodegenerative DiseasesCaspase 6;

机译：晶体结构;CASP6基因;亨廷顿DiseaseNeurodegenerative DiseasesCaspase 6;

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The regulatory mechanism of the caspase 6 pro-domain revealed by crystal structure and biochemical assays

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