Structures of full-length FGFR cancer fusions and disease mutants

全长 FGFR 癌症融合体和疾病突变体的结构

• 批准号: MR/W000369/1
• 负责人: Alexander Breeze
• 金额: $ 104.96万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW000369%2F1
• 关键词: Structures; full; length; FGFR; cancer

Cells receive signals from growth factors when they need to divide and replicate (e.g., during embryonic development, growth, or wound healing). These signals are transmitted from the outside of the cell, where the growth factor binds, to the inside, by receptor tyrosine kinases (RTKs) - proteins that sit within and span across the cell membrane. Although the structures for parts of RTKs are known, high resolution structures of whole (full-length) RTKs have yet to be determined, so our understanding of how the different domains interact to control signalling is incomplete.In this project, we will determine structures of full-length fibroblast growth factor receptors (FGFRs), using cutting-edge atomic-resolution methods such as cryo-electron microscopy and nuclear magnetic resonance spectroscopy. FGFRs, and altered forms of FGRFs that are responsible for several types of human cancers as well as for some developmental disorders, are archetypal RTKs that control processes such as embryonic development, wound healing, and growth of new blood vessels (angiogenesis). FGFRs are normally activated by binding of fibroblast growth factors (FGFs) to their extracellular (outside of the cell) regions, but in some cancers and developmental diseases they can become altered so that they are permanently active even without FGF binding.Understanding the structural connections between the different domains of FGFRs (e.g. extracellular and intracellular parts) is essential if we are to understand how FGFRs and other RTKs function normally - for example, how they are auto-inhibited in the resting state but then become activated. This is particularly the case for a cancer-associated variant of FGFRs whereby part of the FGFR3 gene becomes fused with part of the gene from another protein, TACC3, to generate a hybrid protein that is hyperactivated and also localises to different parts of the cell. These so-called FGFR3-TACC3 fusions are responsible for certain types of glioblastomas (aggressive brain tumours) and some bladder cancers. Understanding at a structural level how the hyperactivation occurs will improve our ability to selectively target these fusion proteins to better treat those cancers for which they are responsible.We also anticipate that these disease-associated variants of FGFRs with aberrant activity are likely to form novel intracellular complexes with a variety of different protein partners. To fully understand how mutations may affect function we must also identify binding partners that can facilitate and regulate signal transduction. To this end another aspect of our research will be to use cross-linking mass spectrometry (XL-MS) in lab-grown cancer cells to identify these new partners and find out how those interactions contribute to the disease process.By improving our knowledge of (normal and disease-altered) FGFR structures and cellular interactions, we aim to understand better why FGFR-targeted drug molecules are effective in some disease settings and less so in others, and how we can then develop more efficacious drug molecules. In summary, our project aims to address the following questions:- Through solving the structures of complete FGFRs and their cancer-associated altered forms (e.g. FGFR-TACC fusions), can we better understand how extracellular signals (such as growth factor binding) are translated into the different intracellular responses generated from activated FGFRs?- What functional complexes do FGFRs form in normal and cancer cells, and what do they tell us about potential new therapeutic drug targeting strategies?

细胞需要分裂和复制（例如，在胚胎发育，生长或伤口愈合过程中），从生长因子中接收信号。这些信号是从细胞外部传播的，在该细胞的外部，生长因子通过受体酪氨酸激酶（RTK）（RTKS） - 位于细胞膜内并跨度的蛋白质结合到内部。尽管已知RTK部分的结构，但尚未确定整个（全长）RTK的高分辨率结构，因此我们对不同域与控制信号的相互作用如何不完整的理解是不完整的。在此项目中，我们将确定结构全长成纤维细胞生长因子受体（FGFR），使用尖端原子分辨率方法，例如冷冻电子显微镜和核磁共振光谱。 FGFR和FGRF的变化形式是负责几种类型的人类癌症以及某些发育障碍的fgrfs，是控制过程的原型RTK，例如胚胎发育，伤口愈合和新血管的生长（血管生成）。 FGFR通常通过成纤维细胞生长因子（FGF）与其细胞外（细胞外）区域的结合而受到激活如果要了解FGFR和其他RTK的正常功能 - 例如，在静息状态下如何自动抑制，但随后激活它们，则必须在FGFR的不同域（例如细胞外和细胞内部件）之间至关重要。 FGFRS的癌症相关变体尤其如此，因此FGFR3基因的一部分从另一种蛋白TaCC3与部分基因融合在一起，从而产生了过度活化的杂化蛋白，并在细胞的不同部分中局部。这些所谓的FGFR3-TACC3融合构成了某些类型的胶质母细胞瘤（侵袭性脑肿瘤）和一些膀胱癌。在结构层面上了解过度激活的发生方式将提高我们有选择地靶向这些融合蛋白以更好地治疗其负责的癌症的能力。我们还预计，这些与异常活性的FGFR的这些相关变体可能形成新型细胞内细胞内细胞内细胞内的变体具有各种不同蛋白质伴侣的复合物。为了充分了解突变如何影响功能，我们还必须确定可以促进和调节信号转导的结合伙伴。为此，我们研究的另一个方面将是在实验室成长的癌细胞中使用交联质谱（XL-MS）来识别这些新伴侣，并找出这些相互作用如何有助于疾病过程。 （正常和改变疾病的）FGFR结构和细胞相互作用，我们旨在更好地理解为什么FGFR靶向的药物分子在某些疾病环境中有效，而在其他疾病环境中则较少，以及如何开发更有效的药物分子。总而言之，我们的项目旨在解决以下问题： - 通过解决完整FGFR及其癌症相关的变化形式（例如FGFR-TACC融合）的结构，我们可以更好地了解细胞外信号（例如生长因子结合）如何是如何翻译成由活化的FGFR产生的不同细胞内反应？ - 正常和癌细胞中FGFRS形成哪些功能复合物，他们告诉我们有关潜在的新型治疗药物靶向策略的什么？

项目成果

Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly.

• DOI: 10.1038/s41467-022-28660-7
• 发表时间: 2022-02-24
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Xu Y;Maya-Martinez R;Guthertz N;Heath GR;Manfield IW;Breeze AL;Sobott F;Foster R;Radford SE
• 通讯作者: Radford SE