CLASS III RECEPTOR TYROSINE KINASES THAT BIND HELICAL-BUNDLE LIGANDS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 跨膜受体缺陷/故障经常导致或促成癌症。调节这些受体有望开发癌症治疗方法，但需要了解激素/生长因子如何通过这些受体发挥作用。KIT是干细胞因子(SCF)的受体，对人类至关重要。KIT功能障碍与胃肠道间质瘤、生殖细胞瘤和急性髓系白血病有关。 干细胞因子(SCF)结合并激活KIT受体，一种III类受体酪氨酸激酶(RTK)，刺激包括黑素生成、配子生成和造血在内的多种过程。KIT激活的失调与许多癌症有关。我们报道了SCF功能核心与KIT的胞外配体结合域结合的2.5A晶体结构。该结构揭示了KIT对SCF的“包裹”识别模式，其中KIT采用弯曲构象，以促进其前三个免疫球蛋白(Ig)样结构域与SCF的相互作用。SCF上的三个表面表位，一个延伸的环，B和C螺旋，以及N-末端片段，接触不同的Kit结构域，其中两个表位在受体结合时发生了较大的构象变化。SCF/KIT复合体揭示了一种独特的RTK二聚化组装，以及四螺旋束细胞因子和Ig家族受体之间的一种新的识别模式。它为理解III类RTK的激活机制提供了一个框架。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Transmembrane receptor defects/malfunctions frequently cause or contribute to cancer. Modulating these receptors holds promises for developing cancer therapies, but understanding how hormones/growth factors act through these receptors is required. KIT, the receptor for Stem Cell Factor (SCF), is essential for humans. Kit malfunctioning is associated with gastrointestinal stromal tumors, germ cell tumors and acute myeloid leukemia. Stem cell factor (SCF) binds to and activates the KIT receptor, a class III receptor tyrosine kinase (RTK), to stimulate diverse processes including melanogenesis, gametogenesis and hematopoeisis. Dysregulation of KIT activation is associated with many cancers. We report a 2.5 A crystal structure of the functional core of SCF bound to the extracellular ligand-binding domains of KIT. The structure reveals a 'wrapping' SCF-recognition mode by KIT, in which KIT adopts a bent conformation to facilitate each of its first three immunoglobulin (Ig)-like domains to interact with SCF. Three surface epitopes on SCF, an extended loop, the B and C helices, and the N-terminal segment, contact distinct KIT domains, with two of the epitopes undergoing large conformational changes upon receptor binding. The SCF/KIT complex reveals a unique RTK dimerization assembly, and a novel recognition mode between four-helix bundle cytokines and Ig-family receptors. It serves as a framework for understanding the activation mechanisms of class III RTKs.