Mechanism for the activation of the anaplastic lymphoma kinase receptor.
Mechanism for the activation of the anaplastic lymphoma kinase receptor.
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DOI：
10.1038/s41586-021-04140-8
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发表时间：
2021-12
期刊：
影响因子：
64.8
通讯作者：
Kalodimos CG
中科院分区：
文献类型：
--
作者：
Reshetnyak AV;Rossi P;Myasnikov AG;Sowaileh M;Mohanty J;Nourse A;Miller DJ;Lax I;Schlessinger J;Kalodimos CG
间变性淋巴瘤激酶（ALK）是一种受体酪氨酸激酶（RTK），调节中枢神经系统的重要功能。ALK基因是染色体易位事件的热点，导致几种融合蛋白，导致各种人类恶性肿瘤。在儿童神经母细胞瘤中发现了ALK的体细胞和生殖系功能获得性突变。ALK由胞外区（ECR）、单个跨膜螺旋和胞内酪氨酸激酶结构域组成。ALK通过ALKAL 1和ALKAL 2配体与其ECR结合而活化，但缺乏ALK-ECR或ALKAL配体的结构信息限制了我们对ALK活化的理解。在这里，我们使用cryo-EM，NMR和X射线晶体学来确定人类ALK二聚化和ALKAL 1和ALKAL 2激活的原子细节。我们的数据揭示了一种新的RTK激活机制，允许二聚体（ALKAL 2）或单体（ALKAL 1）配体的二聚化。这种机制是由一个不寻常的结构的受体-配体复合物。ALK-ECR经历明显的配体诱导重排，并采用平行于膜表面的取向。这种取向通过配体和膜之间的相互作用进一步稳定。我们的研究结果突出了RTK寡聚化和激活机制的多样性。
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) regulating important functions in the central nervous system. The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies. Somatic and germline gain-of-function mutations in ALK were identified in pediatric neuroblastoma. ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain. ALK is activated by the binding of ALKAL1 and ALKAL2 ligands to its ECR, but the lack of structural information for ALK-ECR or ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-EM, NMR, and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a new mechanism for RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor-ligand complex. ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1073/pnas.83.17.6258
发表时间：
1986-09-01
影响因子：
11.1
作者：
GRASBERGER, B;MINTON, AP;METZGER, H
通讯作者：
METZGER, H
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD
DOI：
10.1107/s2059798319011471
发表时间：
2019-10-01
影响因子：
2.2
作者：
Liebschner, Dorothee;Afonine, Pavel V.;Adams, Paul D.
通讯作者：
Adams, Paul D.
影响因子：
7.7
作者：
Lorén, CE;Englund, C;Palmer, RH
通讯作者：
Palmer, RH