Titin kinase is an inactive pseudokinase scaffold that supports MuRF1 recruitment to the sarcomeric M-line.
Titin kinase is an inactive pseudokinase scaffold that supports MuRF1 recruitment to the sarcomeric M-line.
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DOI：
10.1098/rsob.140041
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发表时间：
2014-05
期刊：
影响因子：
5.8
通讯作者：
Mayans O
中科院分区：
文献类型：
--
作者：
Bogomolovas J;Gasch A;Simkovic F;Rigden DJ;Labeit S;Mayans O
横纹肌组织经历适应性重塑以响应机械负荷。该过程涉及肌丝肌联蛋白，特别是其激酶结构域（TK;肌联蛋白激酶），其将机械信号转化为肌原纤维中基因表达的调控途径。TK机械感应似乎由空间抑制其活性位点的C-末端调节尾（CRD）介导。在肌肉功能过程中，牵拉诱导的这条尾巴的展开释放TK抑制并导致其催化活化。然而，TK的细胞途径知之甚少，迄今为止提出的底物仍然存在争议。TK最好的底物是Tcap，这是一种Z盘的小结构蛋白，被认为将TK与肌原纤维发生联系起来。在这里，我们表明，TK是一种假激酶与不可检测的催化水平，因此，Tcap不是它的底物。失活是TK活性位点中的两个非典型残基M34和E147的结果，这两个残基似乎与经典激酶模式不相容。虽然不介导拉伸依赖性磷酸转移，TK结合E3泛素连接酶MuRF1，以应激诱导的方式促进肌节泛素化。鉴于以前的证据MuRF2的相互作用，我们建议TK的细胞作用是作为一个构象调节的支架，功能上耦合的泛素连接酶MuRF1和MuRF2，从而协调肌肉特异性泛素化途径和肌原纤维营养。最后，我们建议，激酶/pseudokinases的进化二分法已经发生在TK样激酶，无脊椎动物的成员是活性酶，但脊椎动物同行执行其信号功能的pseudokinase支架。
Striated muscle tissues undergo adaptive remodelling in response to mechanical load. This process involves the myofilament titin and, specifically, its kinase domain (TK; titin kinase) that translates mechanical signals into regulatory pathways of gene expression in the myofibril. TK mechanosensing appears mediated by a C-terminal regulatory tail (CRD) that sterically inhibits its active site. Allegedly, stretch-induced unfolding of this tail during muscle function releases TK inhibition and leads to its catalytic activation. However, the cellular pathway of TK is poorly understood and substrates proposed to date remain controversial. TK's best-established substrate is Tcap, a small structural protein of the Z-disc believed to link TK to myofibrillogenesis. Here, we show that TK is a pseudokinase with undetectable levels of catalysis and, therefore, that Tcap is not its substrate. Inactivity is the result of two atypical residues in TK's active site, M34 and E147, that do not appear compatible with canonical kinase patterns. While not mediating stretch-dependent phospho-transfers, TK binds the E3 ubiquitin ligase MuRF1 that promotes sarcomeric ubiquitination in a stress-induced manner. Given previous evidence of MuRF2 interaction, we propose that the cellular role of TK is to act as a conformationally regulated scaffold that functionally couples the ubiquitin ligases MuRF1 and MuRF2, thereby coordinating muscle-specific ubiquitination pathways and myofibril trophicity. Finally, we suggest that an evolutionary dichotomy of kinases/pseudokinases has occurred in TK-like kinases, where invertebrate members are active enzymes but vertebrate counterparts perform their signalling function as pseudokinase scaffolds.
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影响因子：
11.8
作者：
Malureanu, Liviu A.;Jeganathan, Karthik B.;Hamada, Masakazu;Wasilewski, Lisa;Davenport, James;van Deursen, Jan M.
通讯作者：
van Deursen, Jan M.
影响因子：
3.4
作者：
Gräter, F;Shen, JH;Grubmüller, H
通讯作者：
Grubmüller, H
DOI：
10.1111/j.1432-1033.1996.454rr.x
发表时间：
1996-12-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Heierhorst, J;Tang, XX;Benian, GM
通讯作者：
Benian, GM
DOI：
10.1074/jbc.m113.479030
发表时间：
2014-01-17
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Candasamy AJ;Haworth RS;Cuello F;Ibrahim M;Aravamudhan S;Krüger M;Holt MR;Terracciano CM;Mayr M;Gautel M;Avkiran M
通讯作者：
Avkiran M
DOI：
10.1073/pnas.1102554108
发表时间：
2011-04-12
影响因子：
11.1
作者：
Hu, Jiancheng;Yu, Haiyang;Shaw, Andrey S.
通讯作者：
Shaw, Andrey S.