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Nature：细胞酶研究将导致更好的心脏病和中风**
来源:科学网
   
Nature：细胞酶研究将导致更好的心脏病和中风**加拿大女王大学的研究揭示了人体内一种细胞酶对心脏病发作和中风之后组织损坏的影响。这一发现将有助于开发新的**疗法，帮助心脏病发作和中风后恢复，同时可减少阿尔茨海默氏症和其他神经变性**的影响。相关论文在线发表于11月20日的《自然》（Nature）杂志。
    实验小组由加拿大蛋白质工程教授PeterDavies领导，他表示：“这真是令人激动，因为这种蛋白质的结构，以及它的抑制剂如何在不损害自身的前提下阻止其活性，一直以来都难以捉摸。”
   在细胞生长和运动所需的重塑蛋白中，人体细胞使用钙蛋白酶(Calpain)来帮助其与其他蛋白质分离。钙离子浓度的异常增高可激活钙蛋白酶。而在心脏病发作和中风时，细胞的血液供应中断，当再度供血时，大量涌入的血液使得细胞内钙离子达到危险的浓度，使钙蛋白酶活性增强，结果给组织造成了很大伤害。研究小组成员RobCampbell表示：“人们不希望酶的激活或关闭完全不受控制。”
   研究还显示了当钙蛋白酶被钙离子激活后，另一种蛋白质——钙蛋白酶抑制蛋白（calpastatin）如何阻止了钙蛋白酶的活性。Campbell和博士生RachelHanna能够确定钙绑定的钙蛋白酶的结构，并发现了钙蛋白酶抑制蛋白如何在不受破坏的同时抑制钙蛋白酶。这将有助于设计新**，防止过度激活的钙蛋白酶对组织造成破坏。（创赛新闻中心canspecsci.com）

创赛推荐原始出处：

Nature，456, 409-412，Rachel A. Hanna，Peter L. Davies
Calcium-bound structure of calpain and its mechanism of inhibitionby calpastatin
Rachel A. Hanna1, Robert L. Campbell1 & Peter L. Davies1
    1 Department of Biochemistry, Queen'sUniversity, Kingston, Ontario, Canada K7L 3N6
Calpains are non-lysosomal calcium-dependent cysteine proteinasesthat selectively cleave proteins in response to calcium signals1and thereby control cellular functions such as cytoskeletalremodelling, cell cycle progression, gene expression and apoptoticcell death2, 3, 4. In mammals, the two best-characterized membersof the calpain family, calpain 1 and calpain 2 (-calpain andm-calpain, respectively), are ubiquitously expressed. The activityof calpains is tightly controlled by the endogenous inhibitorcalpastatin, which is an intrinsically unstructured protein capableof reversibly binding and inhibiting four molecules of calpain, butonly in the presence of calcium5, 6. To date, the mechanism ofinhibition by calpastatin and the basis for its absolutespecificity have remained speculative7, 8, 9. It was not clear howthis unstructured protein inhibits calpains without being cleaveditself, nor was it known how calcium induced changes thatfacilitated the binding of calpastatin to calpain. Here we reportthe 2.4-?-resolution crystal structure of the calcium-bound calpain2 heterodimer bound by one of the four inhibitory domains ofcalpastatin. Calpastatin is seen to inhibit calpain by occupyingboth sides of the active site cleft. Although the inhibitor passesthrough the active site cleft it escapes cleavage in a novel mannerby looping out and around the active site cysteine. The inhibitorydomain of calpastatin recognizes multiple lower affinity sitespresent only in the calcium-bound form of the enzyme, resulting inan interaction that is tight, specific and calcium dependent. Thiscrystal structure, and that of a related complex10, also reveal theconformational changes that calpain undergoes on binding calcium,which include opening of the active site cleft and movement of thedomains relative to each other to produce a more compactenzyme.
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