RET Recognition of GDNF-GFRaα1 Ligand by a Composite Binding Site Promotes Membrane-Proximal Self-Association
RET Recognition of GDNF-GFRaα1 Ligand by a Composite Binding Site Promotes Membrane-Proximal Self-Association
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DOI：
10.1016/j.celrep.2014.08.040
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发表时间：
2014-09-25
期刊：
影响因子：
8.8
通讯作者：
McDonald, Neil Q.
中科院分区：
文献类型：
--
作者：
Goodman, Kerry M.;Kjaer, Svend;McDonald, Neil Q.
RET受体酪氨酸激酶对脊椎动物的发育至关重要，并与多种人类疾病有关。RET结合由GDNF家族配体和GFR α辅助受体组成的细胞表面两部分配体，导致RET跨膜信号传导。我们提出了一个基于电子显微镜（EM）和低角度x射线散射（SAXS）数据的RET细胞外结构域（RETECD）、GDNF和GFR α 1三元配合物的混合结构模型，定义了配体识别的基础。RET - ECD通过包含四个离散接触位点的复合结合位点包裹二聚体配体复合物。GFR α 1介导的接触是至关重要的，特别是靠近不变的RET钙结合位点，而GDNF很少直接接触，这解释了不同的配体/辅助受体对是如何调节的。RET - ECD富含半胱氨酸结构域（CRD）与两种配体成分接触，并使三种不同抗体表位发生同型膜-近端相互作用。这些crd介导的相互作用的耦合提出了配体诱导的RET激活和配体独立的致癌调节模型。
The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a GFR alpha coreceptor, resulting in RET transmembrane signaling. We present a hybrid structural model, derived from electron microscopy (EM) and low-angle X-ray scattering (SAXS) data, of the RET extracellular domain (RETECD), GDNF, and GFR alpha 1 ternary complex, defining the basis for ligand recognition. RET ECD envelopes the dimeric ligand complex through a composite binding site comprising four discrete contact sites. The GFR alpha 1-mediated contacts are crucial, particularly close to the invariant RET calcium-binding site, whereas few direct contacts are made by GDNF, explaining how distinct ligand/coreceptor pairs are accommodated. The RET ECD cysteine-rich domain (CRD) contacts both ligand components and makes homotypic membrane-proximal interactions occluding three different antibody epitopes. Coupling of these CRD-mediated interactions suggests models for ligand-induced RET activation and ligand-independent oncogenic deregulation.