CLASS III RECEPTOR TYROSINE KINASES THAT BIND HELICAL-BUNDLE LIGANDS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 跨膜受体缺陷/功能障碍经常导致或促成癌症。调节这些受体有望开发癌症疗法，但需要了解激素/生长因子如何通过这些受体起作用。KIT是干细胞因子（SCF）的受体，对人类至关重要。试剂盒故障与胃肠道间质瘤、生殖细胞肿瘤和急性髓性白血病有关。 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），以刺激包括黑素生成、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相关。我们报告了一个2.5 A晶体结构的SCF的功能核心结合到细胞外配体结合域的KIT。该结构揭示了KIT的“包裹”SCF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）样结构域中的每一个与SCF相互作用。SCF上的三个表面表位，一个延伸环，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后发生大的构象变化。SCF/KIT复合物揭示了独特的RTK二聚体组装，以及四螺旋束细胞因子与Ig家族受体之间的新型识别模式。它作为理解III类RTK激活机制的框架。

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.