（封面圖片：鉛筆描繪的圖片中,，CASK激酶被表示成一只鳳凰，這只被認(rèn)為在進(jìn)化的火焰中已經(jīng)死去的鳳凰卻以一種出人意料的形式最終實(shí)現(xiàn)重生,。圖片提供：Manu Sharma）
鈣/鈣調(diào)蛋白依賴性絲氨酸蛋白激酶（calcium/calmodulin-dependent serine protein kinase CASK）是一種獨(dú)特的膜相關(guān)鳥苷酸激酶（membrane associated guanylate kinase MAGUK）,。CASK具有多個不同的蛋白質(zhì)結(jié)合結(jié)構(gòu)域，除了典型的MAGUK域之外,，它還擁有一個氨基末端（N-terminal）鈣調(diào)蛋白激酶（CaM-kinase）域,。科學(xué)家通常認(rèn)為,，CASK鈣調(diào)蛋白激酶域是一個催化非活性假性激酶域（pseudokinase）,，因?yàn)槠淙鄙俳Y(jié)合Mg2+規(guī)范的DFG模體（motif），而激酶催化的磷酸轉(zhuǎn)移需要利用鎂離子Mg2+作為作用子,，因而這種模體對于激酶的活性是必不可少的,。
在2008年4月18日出版的《細(xì)胞》（Cell）上,，來自美國和德國的一組科學(xué)家證明以上的猜想可能是錯誤的，他們發(fā)表文章稱,，CASK能在缺少M(fèi)g2+結(jié)合的情況下起到活性蛋白激酶的作用,，這表明CASK鈣調(diào)蛋白激酶域即使在缺乏Mg2+的條件下也是一種擁有活性的激酶。
研究中,，科學(xué)家們通過高分辨晶體結(jié)構(gòu)發(fā)現(xiàn),，CASK鈣調(diào)蛋白激酶域利用一種活性構(gòu)造來實(shí)現(xiàn)在缺少M(fèi)g2+情況下的三磷酸腺苷ATP結(jié)合，并催化磷酸轉(zhuǎn)移（phosphotransfer）,。研究人員還發(fā)現(xiàn),，CASK鈣調(diào)蛋白激酶域能使其自身磷酸化，并磷酸化至少一個生理作用子neurexin-1蛋白,，它們能通過類似調(diào)節(jié)神經(jīng)元活性的方式來使neurexin-1磷酸化,。Neurexin-1屬于neurexin蛋白家族，這是一類神經(jīng)細(xì)胞表面蛋白,，主要在細(xì)胞識別以及細(xì)胞黏附方面起作用,，并且可能參與細(xì)胞信號的傳導(dǎo)等生理過程。因此,，以上研究數(shù)據(jù)顯示,，其它的假性激酶同樣能實(shí)現(xiàn)催化活性，這些假性激酶占到整個蛋白激酶組（kinome）的10%,。（科學(xué)網(wǎng) 何宏輝/編譯）
生物谷推薦原始出處：
（Cell）,，Vol 133, 328-339, 18 April 2008，Konark Mukherjee, Markus C. Wahl
CASK Functions as a Mg2+-Independent Neurexin Kinase
Konark Mukherjee,1,2, Manu Sharma,1 Henning Urlaub,3 Gleb P. Bourenkov,5 Reinhard Jahn,2 Thomas C. Südhof,1, and Markus C. Wahl4,6,
1 Department of Neuroscience, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9111, USA
2 Department of Neurobiology, Max-Planck-Institute for Biophysical Chemistry, Am Faßberg 11, D-37077 Göttingen, Germany
3 Research Group of Bioanalytical Mass Spectrometry, Max-Planck-Institute for Biophysical Chemistry, Am Faßberg 11, D-37077 Göttingen, Germany
4 Research Group of X-Ray Crystallography, Max-Planck-Institute for Biophysical Chemistry, Am Faßberg 11, D-37077 Göttingen, Germany
5 EMBL Hamburg c/o Deutsches Elektronensynchrotron, Notkestraße 85, D-22603 Hamburg, Germany
6 Georg-August-University Göttingen, Department of Medicine, Justus-von-Liebig-Weg 11, D-37077 Göttingen, Germany
Summary
CASK is a unique MAGUK protein that contains an N-terminal CaM-kinase domain besides the typical MAGUK domains. The CASK CaM-kinase domain is presumed to be a catalytically inactive pseudokinase because it lacks the canonical DFG motif required for Mg2+ binding that is thought to be indispensable for kinase activity. Here we show, however, that CASK functions as an active protein kinase even without Mg2+ binding. High-resolution crystal structures reveal that the CASK CaM-kinase domain adopts a constitutively active conformation that binds ATP and catalyzes phosphotransfer without Mg2+. The CASK CaM-kinase domain phosphorylates itself and at least one physiological interactor, the synaptic protein neurexin-1, to which CASK is recruited via its PDZ domain. Thus, our data indicate that CASK combines the scaffolding activity of MAGUKs with an unusual kinase activity that phosphorylates substrates recuited by the scaffolding activity. Moreover, our study suggests that other pseudokinases (10% of the kinome) could also be catalytically active.
