Martin Eleyna M, Zuidscherwoude Malou, Morán Luis A, Di Ying, García Angel, Watson Steve P
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham.
Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade De Santiago De Compostela, Spain.
Platelets. 2021 Aug 18;32(6):733-743. doi: 10.1080/09537104.2021.1906407. Epub 2021 Apr 5.
The platelet C-type lectin-like receptor CLEC-2 drives inflammation-driven venous thrombosis in mouse models of thrombo-inflammatory disease with a minimal effect on hemostasis identifying it as a target for a new class of antiplatelet agent. Here, we discuss how the protein structure and dynamic arrangement of CLEC-2 on the platelet membrane helps the receptor, which has a single YxxL motif (known as a hemITAM), to trigger intracellular signaling. CLEC-2 exists as a monomer and homo-dimer within resting platelets and forms higher-order oligomers following ligand activation, a process that is mediated by the multivalent nature of its ligands and the binding of the tandem SH2 domains of Syk to the phosphorylated hemITAM and concomitantly to PIP or PIP to localize it to the membrane. We propose that a low level of active Syk is present at the membrane in resting platelets due to phosphorylation by Src family kinases and that clustering of receptors disturbs the equilibrium between kinases and phosphatases, triggering phosphorylation of the CLEC-2 hemITAM and recruitment of Syk. Knowledge of the structure of CLEC-2 and the mechanism of platelet activation has important implications for development of therapeutics.
血小板C型凝集素样受体CLEC-2在血栓炎症性疾病的小鼠模型中驱动炎症驱动的静脉血栓形成，对止血的影响最小，这使其成为一类新型抗血小板药物的靶点。在此，我们讨论CLEC-2在血小板膜上的蛋白质结构和动态排列如何帮助该受体（其具有单个YxxL基序，即hemITAM）触发细胞内信号传导。CLEC-2在静息血小板中以单体和同二聚体形式存在，并在配体激活后形成高阶寡聚体，这一过程由其配体的多价性质以及Syk的串联SH2结构域与磷酸化的hemITAM结合并同时与PIP或PIP2结合以将其定位到膜上介导。我们提出，由于Src家族激酶的磷酸化作用，静息血小板膜上存在低水平的活性Syk，并且受体的聚集会扰乱激酶和磷酸酶之间的平衡，触发CLEC-2 hemITAM的磷酸化并募集Syk。了解CLEC-2的结构和血小板激活机制对治疗药物的开发具有重要意义。
