Cooperative autoinhibition and multi-level activation mechanisms of calcineurin  

作　　者：Sheng-Jie Li Jue Wang Lei Ma Chang Lu Jie Wang Jia-Wei Wu Zhi-Xin Wang 

机构地区：[1]MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084, China [2]Institute of Bio- physics, Chinese Academy of Sciences, Beijing 100101, China [3]Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China

出　　处：《Cell Research》2016年第3期336-349,共14页细胞研究（英文版）

摘　　要：The Ca2＋/calmodulin-dependent protein phosphatase calcineurin （CN）, a heterodimer composed of a catalytic subunit A and an essential regulatory subunit B, plays critical functions in various cellular processes such as cardiac hypertrophy and T cell activation. It is the target of the most widely used immunosuppressants for transplantation, tacrolimus （FKS06） and cyclosporin A. However, the structure of a large part of the CNA regulatory region remains to be determined, and there has been considerable debate concerning the regulation of CN activity. Here, we report the crystal structure of full-length CN （β isoform）, which revealed a novel autoinhibitory segment （AIS） in addition to the well-known autoinhibitory domain （AID）. The AIS nestles in a hydrophobic intersubunit groove, which over- laps the recognition site for substrates and immunosuppressant-immunophilin complexes. Indeed, disruption of this AIS interaction results in partial stimulation of CN activity. More importantly, our biochemical studies demonstrate that calmodulin does not remove AID from the active site, but only regulates the orientation of AID with respect to the catalytic core, causing incomplete activation of CN. Our findings challenge the current model for CN activation, and provide a better understanding of molecular mechanisms of CN activity regulation.

关 键 词：structure of full-length calcineurin bipartite autoinhibition multi-level activation mechanism of immunosup-pressant stimulation regulation of calcineurin 

分 类 号：Q55[生物学—生物化学] TP317.1[自动化与计算机技术—计算机软件与理论]