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首页> 外文期刊>Journal of Molecular Biology >Structure of the human protein kinase CK2 catalytic subunit CK2alpha' and interaction thermodynamics with the regulatory subunit CK2beta.
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Structure of the human protein kinase CK2 catalytic subunit CK2alpha' and interaction thermodynamics with the regulatory subunit CK2beta.

机译：人蛋白激酶CK2催化亚基CK2alpha'的结构以及与调节性亚基CK2beta的相互作用热力学。

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摘要

Protein kinase CK2 (formerly "casein kinase 2") is composed of a central dimer of noncatalytic subunits (CK2beta) binding two catalytic subunits. In humans, there are two isoforms of the catalytic subunit (and an additional splicing variant), one of which (CK2alpha) is well characterized. To supplement the limited biochemical knowledge about the second paralog (CK2alpha'), we developed a well-soluble catalytically active full-length mutant of human CK2alpha', characterized it by Michaelis-Menten kinetics and isothermal titration calorimetry, and determined its crystal structure to a resolution of 2 A. The affinity of CK2alpha' for CK2beta is about 12 times lower than that of CK2alpha and is less driven by enthalpy. This result fits the observation that the beta4/beta5 loop, a key element of the CK2alpha/CK2beta interface, adopts an open conformation in CK2alpha', while in CK2alpha, it opens only after assembly with CK2beta. The open beta4/beta5 loop in CK2alpha' is stabilized by two elements that are absent in CK2alpha: (1) the extension of the N-terminal beta-sheet by an additional beta-strand, and (2) the filling of a conserved hydrophobic cavity between the beta4/beta5 loop and helix alphaC by a tryptophan residue. Moreover, the interdomain hinge region of CK2alpha' adopts a fully functional conformation, while unbound CK2alpha is often found with a nonproductive hinge conformation that is overcome only by CK2beta binding. Taken together, CK2alpha' exhibits a significantly lower affinity for CK2beta than CK2alpha; moreover, in functionally critical regions, it is less dependent on CK2beta to obtain a fully functional conformation.
机译：蛋白激酶CK2（以前称为“酪蛋白激酶2”）由结合两个催化亚基的非催化亚基（CK2beta）的中央二聚体组成。在人类中，催化亚基有两种同工型（和另外一个剪接变体），其中一种（CK2α）具有良好的特征。为了补充有关第二个对位物（CK2alpha'）的有限的生化知识，我们开发了人CK2alpha'的可溶性催化活性全长突变体，通过Michaelis-Menten动力学和等温滴定量热法对其进行了表征，并确定了其晶体结构分辨率为2A。CK2alpha'对CK2beta的亲和力比CK2alpha低约12倍，并且不受焓的驱动。该结果符合以下观察结果：beta4 / beta5环是CK2alpha / CK2beta接口的关键元件，在CK2alpha'中采用开放构象，而在CK2alpha中，仅在与CK2beta组装后才开放。 CK2alpha'中开放的beta4 / beta5环由CK2alpha中不存在的两个元素稳定：（1）N末端β-折叠层通过额外的β-链延伸，（2）保守的疏水性填充色氨酸残基位于beta4 / beta5环和螺旋alphaC之间的空腔。此外，CK2alpha'的域间铰链区采用完全功能性构象，而未结合的CK2alpha常常具有非生产性铰链构象，只有通过CK2beta结合才能克服。综上所述，CK2alpha'对CK2beta的亲和力明显低于CK2alpha。此外，在功能关键区域中，获得完整功能构象的依赖性较小。

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