两学者《Nature》修正蛋白活性理论

　　

生物通报道，来自Rutgers大学化学与生物化学系的两位学者近期在蛋白活性研究上获得新观点，相关成果文章Dynamic activation of an allosteric regulatory protein发表在Nature杂志上。

 

文章通讯作者是Charalampos G. Kalodimos，第一作者是Shiou-Ru Tzeng。

 

别构调节（Allosteric regulation，源自希腊语 allos——“其他”、stereos——“固态(物体)”）是酶活性调节的一种机制，也称为变构调节。其原理为，一些酶除了有活性中心外，还有所谓别构中心，该中心可与配体（有时为底物）结合从而使酶的构象发生改变，影响到酶活性中心与底物的亲和力以及酶的活性。

 

Charalampos G. Kalodimos和Shiou-Ru Tzeng的一项新研究表明，认为别构蛋白的活性纯粹由结构调控的观点应当予以修正，应该将来自蛋白动态的一个经常占支配地位的贡献包括进去。

 

Shiou-Ru Tzeng 和 Charalampos Kalodimos对与“降解物激活蛋白”（CAP）相结合的环AMP进行了定性。CAP是被经常用作变构模型的一个转录激活蛋白。他们出乎意料地发现，即便是当处在一个从结构上来讲没有活性的构形时，CAP也能被蛋白动态的变化所激活，以便与配体（DNA）结合。

 

这些数据强烈地显示，别构蛋白的活性不仅仅受结构的影响，它同时也受蛋白动态变化的影响，经典的别构蛋白活性纯粹由结构调控的观点应该受到修正。

 

延伸阅读

别构部位的概念是1963年由法国科学家J．莫诺等提出来的。影响蛋白质活性的物质称为别构配体或别构效应物。该物质作用于蛋白质的某些部位而发生的相互影响称为协同性。抑制蛋白质活力的现象称为负协同性，该物质称为负效应物。增加活力的现象称为正协同性，该物质称为正效应物。受别构效应调节的蛋白质称为别构蛋白质，如果是酶，则称为别构酶。

 

在50年代后期，先后发现某些氨基酸对催化其合成途径第一步反应的酶有抑制作用，这种现象称为反馈抑制。起抑制作用的物质与该酶的底物在结构上完全不同，这种结构不同于底物的抑制物是结合于酶的活性部位以外的其他部位，即别构部位而影响酶的活力的。

（生物通 小茜）

生物通推荐原文检索

Dynamic activation of an allosteric regulatory protein

Shiou-Ru Tzeng1,2 & Charalampos G. Kalodimos1,2

 

Department of Chemistry & Chemical Biology,

Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA

Correspondence to: Charalampos G. Kalodimos1,2 Correspondence and requests for materials should be addressed to C.G.K. (Email: [e-mail]).

 

【Abstract】

Allosteric regulation is used as a very efficient mechanism to control protein activity in most biological processes, including signal transduction, metabolism, catalysis and gene regulation1, 2, 3, 4, 5, 6. Allosteric proteins can exist in several conformational states with distinct binding or enzymatic activity. Effectors are considered to function in a purely structural manner by selectively stabilizing a specific conformational state, thereby regulating protein activity. Here we show that allosteric proteins can be regulated predominantly by changes in their structural dynamics. We have used NMR spectroscopy and isothermal titration calorimetry to characterize cyclic AMP (cAMP) binding to the catabolite activator protein (CAP), a transcriptional activator that has been a prototype for understanding effector-mediated allosteric control of protein activity7. cAMP switches CAP from the 'off' state (inactive), which binds DNA weakly and non-specifically, to the 'on' state (active), which binds DNA strongly and specifically. In contrast, cAMP binding to a single CAP mutant, CAP-S62F, fails to elicit the active conformation; yet, cAMP binding to CAP-S62F strongly activates the protein for DNA binding. NMR and thermodynamic analyses show that despite the fact that CAP-S62F-cAMP2 adopts the inactive conformation, its strong binding to DNA is driven by a large conformational entropy originating in enhanced protein motions induced by DNA binding. The results provide strong evidence that changes in protein motions may activate allosteric proteins that are otherwise structurally inactive.