Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer
Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer
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DOI：
10.1021/acs.jcim.3c00926
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发表时间：
2023-09-11
影响因子：
5.6
通讯作者：
Lomize，Andrei L.
中科院分区：
文献类型：
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作者：
Pogozheva，Irina D.;Cherepanov，Stanislav;Lomize，Andrei L.
同型二聚体1类细胞因子受体包括促红细胞生成素（EPOR）、促血小板生成素（TPOR）、粒细胞集落刺激因子3（CSF 3R）、生长激素（GHR）和催乳素受体（PRLR）。这些细胞表面单次跨膜（TM）糖蛋白调节细胞生长、增殖和分化并诱导肿瘤发生。活性TM信号传导复合物由受体同二聚体、与受体胞外域结合的一个或两个配体以及与受体胞内域组成性缔合的Janus激酶2（JAK 2）的两个分子组成。虽然除了TPOR之外，已经获得了所有受体的可溶性细胞外结构域与配体的晶体结构，但是对激活下游JAK-STAT信号传导途径的完整TM复合物的结构和动力学知之甚少。通过使用AlphaFold多聚体，在这里生成了五种具有细胞因子和JAK 2的人类受体复合物的三维模型。考虑到复合物的大尺寸（从3220到4074个残基），建模需要从较小的部分逐步组装，通过与已发表的实验数据进行比较来选择和验证模型。活性和非活性复合物的建模支持一般活化机制，其涉及配体与单体受体结合，随后受体二聚化和受体TM α-螺旋的旋转运动，导致相关JAK 2亚基的接近、二聚化和活化。提出了两种艾曲泊帕分子与活性TPOR二聚体TM α-螺旋的结合模式。该模型还有助于阐明致癌突变的分子基础，可能涉及一个非经典的激活途径。在质膜的外显脂质中平衡的模型是公开可用的。
Homodimeric class 1 cytokine receptors include the erythropoietin (EPOR), thrombopoietin (TPOR), granulocyte colony-stimulating factor 3 (CSF3R), growth hormone (GHR), and prolactin receptors (PRLR). These cell-surface single-pass transmembrane (TM) glycoproteins regulate cell growth, proliferation, and differentiation and induce oncogenesis. An active TM signaling complex consists of a receptor homodimer, one or two ligands bound to the receptor extracellular domains, and two molecules of Janus Kinase 2 (JAK2) constitutively associated with the receptor intracellular domains. Although crystal structures of soluble extracellular domains with ligands have been obtained for all of the receptors except TPOR, little is known about the structure and dynamics of the complete TM complexes that activate the downstream JAK-STAT signaling pathway. Three-dimensional models of five human receptor complexes with cytokines and JAK2 were generated here by using AlphaFold Multimer. Given the large size of the complexes (from 3220 to 4074 residues), the modeling required a stepwise assembly from smaller parts, with selection and validation of the models through comparisons with published experimental data. The modeling of active and inactive complexes supports a general activation mechanism that involves ligand binding to a monomeric receptor followed by receptor dimerization and rotational movement of the receptor TM α-helices, causing proximity, dimerization, and activation of associated JAK2 subunits. The binding mode of two eltrombopag molecules to the TM α-helices of the active TPOR dimer was proposed. The models also help elucidate the molecular basis of oncogenic mutations that may involve a noncanonical activation route. Models equilibrated in explicit lipids of the plasma membrane are publicly available.