Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria.
Medical University of Vienna, Center for Medical Biochemistry, Vienna, Austria.
Elife. 2023 Jul 20;12:e88210. doi: 10.7554/eLife.88210.
Phosphorylation of proteins is a ubiquitous mechanism of regulating their function, localization, or activity. Protein kinases, enzymes that use ATP to phosphorylate protein substrates are, therefore, powerful signal transducers in eukaryotic cells. The mechanism of phosphoryl-transfer is universally conserved among protein kinases, which necessitates the tight regulation of kinase activity for the orchestration of cellular processes with high spatial and temporal fidelity. In response to a stimulus, many kinases enhance their own activity by autophosphorylating a conserved amino acid in their activation loop, but precisely how this reaction is performed is controversial. Classically, kinases that autophosphorylate their activation loop are thought to perform the reaction in , mediated by transient dimerization of their kinase domains. However, motivated by the recently discovered regulation mechanism of activation loop -autophosphorylation by a kinase that is autoinhibited in , we here review the various mechanisms of autoregulation that have been proposed. We provide a framework for critically evaluating biochemical, kinetic, and structural evidence for protein kinase dimerization and autophosphorylation, and share some thoughts on the implications of these mechanisms within physiological signaling networks.
蛋白质的磷酸化是调节其功能、定位或活性的普遍机制。蛋白激酶是利用 ATP 将蛋白质底物磷酸化的酶，因此是真核细胞中强大的信号转导因子。磷酸转移的机制在蛋白激酶中普遍保守，这就需要严格调节激酶活性，以高度精确的时空保真度来协调细胞过程。作为对刺激的反应，许多激酶通过自身磷酸化其激活环中的保守氨基酸来增强自身活性，但该反应的确切执行方式存在争议。经典上，被认为通过激酶结构域的瞬时二聚化来进行自身磷酸化的激酶，在介导其活性环的磷酸化反应。然而，受最近发现的一种激酶的激活环 - 自身磷酸化的调节机制的启发，该激酶在自动抑制时是自身抑制的，我们在这里回顾了所提出的各种自身调节机制。我们提供了一个框架，用于批判性地评估生化、动力学和结构证据，以支持蛋白激酶二聚化和自身磷酸化，并就这些机制在生理信号网络中的意义分享一些想法。
