Structural basis for ligand reception by anaplastic lymphoma kinase.
Structural basis for ligand reception by anaplastic lymphoma kinase.
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DOI：
10.1038/s41586-021-04141-7
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发表时间：
2021-12
期刊：
影响因子：
64.8
通讯作者：
Klein DE
中科院分区：
文献类型：
--
作者：
Li T;Stayrook SE;Tsutsui Y;Zhang J;Wang Y;Li H;Proffitt A;Krimmer SG;Ahmed M;Belliveau O;Walker IX;Mudumbi KC;Suzuki Y;Lax I;Alvarado D;Lemmon MA;Schlessinger J;Klein DE
原癌基因间变性淋巴瘤激酶（ALK）是一种受体酪氨酸激酶（RTK），主要在发育中的神经系统中表达。发育后，ALK活性与学习和记忆相关。ALK还可以控制能量消耗，抑制ALK可以预防饮食诱导的肥胖。异常的ALK信号传导导致许多癌症。特别是，全长ALK是儿科神经母细胞瘤的重要驱动因素，在儿科神经母细胞瘤中，ALK发生突变或被配体激活。在这里，我们报告了ALK的不寻常的细胞外甘氨酸丰富结构域（GRD）的晶体结构，该结构域通过与活化肽（ALKAL）结合来调节受体活性。将ALK的GRD与其配体融合在一起，使我们能够捕获二聚体受体复合物，揭示ALK如何对其调节配体作出反应。我们发现GRD中的重复甘氨酸意外地形成刚性螺旋，将主要配体结合位点与介导ALK二聚化的远端聚甘氨酸延伸环（PXL）分开。一个受体的PXL通过与配体结合的第二受体相互作用而充当复合物“传感器”。ALK激活可通过PXL突变或使用PXL靶向抗体消除。总之，我们的研究结果解释了ALK如何使用一种不寻常的结构进行调控，并为ALK表达癌症（如儿童神经母细胞瘤）提供了新的治疗机会。
The proto-oncogene Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase (RTK) expressed primarily in the developing nervous system. After development, ALK activity is associated with learning and memory. ALK also controls energy expenditure and ALK inhibition can prevent diet-induced obesity. Aberrant ALK signaling causes numerous cancers. In particular, full length ALK is an important driver in pediatric neuroblastoma, where it is either mutated or activated by ligand. Here we report crystal structures of ALK’s unusual extracellular glycine-rich domain (GRD), which regulates receptor activity by binding to activating peptides (ALKALs). Fusing ALK’s GRD together with its ligand allowed us to capture a dimeric receptor complex that reveals how ALK responds to its regulatory ligands. We show that repetitive glycines in the GRD unexpectedly form rigid helices that separate the major ligand-binding site from a distal poly-glycine extension loop (PXL) that mediates ALK dimerization. The PXL of one receptor acts as a complex ‘sensor’ by interacting with a ligand bound second receptor. ALK activation can be abolished through PXL mutation or with PXL targeting antibodies. Together, our results explain how ALK uses an unusual architecture for its regulation, and suggest new therapeutic opportunities for ALK-expressing cancers like pediatric neuroblastoma.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
2.7
作者：
Qin, Lan-Ying;Ruan, Zheming;Poss, Michael A.
通讯作者：
Poss, Michael A.
影响因子：
64.8
作者：
Mosse, Yael P.;Laudenslager, Marci;Longo, Luca;Cole, Kristina A.;Wood, Andrew;Attiyeh, Edward F.;Laquaglia, Michael J.;Sennett, Rachel;Lynch, Jill E.;Perri, Patrizia;Laureys, Genevieve;Speleman, Frank;Kim, Cecilia;Hou, Cuiping;Hakonarson, Hakon;Torkamani, Ali;Schork, Nicholas J.;Brodeur, Garrett M.;Tonini, Gian P.;Rappaport, Eric;Devoto, Marcella;Maris, John M.
通讯作者：
Maris, John M.
DOI：
10.15252/embj.2020105784
发表时间：
2021-02-01
期刊：
The EMBO journal
影响因子：
--
作者：
Borenäs M;Umapathy G;Lai WY;Lind DE;Witek B;Guan J;Mendoza-Garcia P;Masudi T;Claeys A;Chuang TP;El Wakil A;Arefin B;Fransson S;Koster J;Johansson M;Gaarder J;Van den Eynden J;Hallberg B;Palmer RH
通讯作者：
Palmer RH
影响因子：
64.8
作者：
Reshetnyak AV;Rossi P;Myasnikov AG;Sowaileh M;Mohanty J;Nourse A;Miller DJ;Lax I;Schlessinger J;Kalodimos CG
通讯作者：
Kalodimos CG