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Nature：細胞酶研究將導致更好的心臟病和中風**
來源:科學網
   
Nature：細胞酶研究將導致更好的心臟病和中風**加拿大女王大學的研究揭示了人體內一種細胞酶對心臟病發作和中風之后組織損壞的影響。這一發現將有助于開發新的**療法，幫助心臟病發作和中風后恢復，同時可減少阿爾茨海默氏癥和其他神經變性**的影響。相關論文在線發表于11月20日的《自然》（Nature）雜志。
    實驗小組由加拿大蛋白質工程教授PeterDavies領導，他表示：“這真是令人激動，因為這種蛋白質的結構，以及它的抑制劑如何在不損害自身的前提下阻止其活性，一直以來都難以捉摸?！?br>   在細胞生長和運動所需的重塑蛋白中，人體細胞使用鈣蛋白酶(Calpain)來幫助其與其他蛋白質分離。鈣離子濃度的異常增高可激活鈣蛋白酶。而在心臟病發作和中風時，細胞的血液供應中斷，當再度供血時，大量涌入的血液使得細胞內鈣離子達到危險的濃度，使鈣蛋白酶活性增強，結果給組織造成了很大傷害。研究小組成員RobCampbell表示：“人們不希望酶的激活或關閉完全不受控制?！?br>   研究還顯示了當鈣蛋白酶被鈣離子激活后，另一種蛋白質——鈣蛋白酶抑制蛋白（calpastatin）如何阻止了鈣蛋白酶的活性。Campbell和博士生RachelHanna能夠確定鈣綁定的鈣蛋白酶的結構，并發現了鈣蛋白酶抑制蛋白如何在不受破壞的同時抑制鈣蛋白酶。這將有助于設計新**，防止過度激活的鈣蛋白酶對組織造成破壞。（創賽新聞中心canspecsci.com）

創賽推薦原始出處：

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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