Bradshaw William J, Harris Gemma, Gileadi Opher, Katis Vittorio L
Alzheimer's Research UK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine Research Building, Old Road Campus, University of Oxford, Oxford OX3 7FZ, UK.
Research Complex at Harwell, Rutherford Appleton Laboratory, Harwell Campus, Didcot OX11 0FA, UK.
Structure. 2024 Dec 5;32(12):2337-2351.e4. doi: 10.1016/j.str.2024.09.024. Epub 2024 Oct 22.
Spleen tyrosine kinase (SYK) is central to adaptive and innate immune signaling. It features a regulatory region containing tandem SH2 (tSH2) domains separated by a helical "hinge" segment keeping SYK inactive by associating with the kinase domain. SYK activation is triggered when the tSH2 domains bind to a phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) found on receptor tails. Past mutational studies have indicated that ITAM binding disrupts the hinge-kinase interaction, leading to SYK phosphorylation and activation. However, the mechanism of this process is unclear, as the ITAM interaction occurs far from the hinge region. We have determined crystal structures of three phospho-ITAMs in complex with the tSH2 domains, revealing a highly conserved binding mechanism. These structures, together with mutational studies and biophysical analyses, reveal that phospho-ITAM binding restricts SH2 domain movement and causes allosteric changes in the hinge region. These changes are not compatible with the association of the kinase domain, leading to kinase activation.
脾酪氨酸激酶（SYK）在适应性免疫和先天性免疫信号传导中起核心作用。它具有一个调节区域，该区域包含串联的SH2（tSH2）结构域，由一个螺旋“铰链”段隔开，通过与激酶结构域结合使SYK处于无活性状态。当tSH2结构域与受体尾部发现的磷酸化基于免疫受体酪氨酸的激活基序（ITAM）结合时，SYK激活被触发。过去的突变研究表明，ITAM结合会破坏铰链-激酶相互作用，导致SYK磷酸化和激活。然而，这一过程的机制尚不清楚，因为ITAM相互作用发生在远离铰链区域的地方。我们已经确定了三种磷酸化ITAM与tSH2结构域复合物的晶体结构，揭示了一种高度保守的结合机制。这些结构，连同突变研究和生物物理分析，表明磷酸化ITAM结合限制了SH2结构域的运动，并导致铰链区域的变构变化。这些变化与激酶结构域的结合不相容，从而导致激酶激活。
