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?

细胞在需要分裂和复制时从生长因子接收信号（例如，在胚胎发育、生长或伤口愈合期间）。这些信号通过受体酪氨酸激酶（RTK）--位于细胞膜内并跨越细胞膜的蛋白质--从细胞外（生长因子在细胞外结合）传递到细胞内。虽然RTK的部分的结构是已知的，但是整体的高分辨率结构是不可能的。RTKs（全长）尚未确定，因此我们对不同结构域如何相互作用以控制信号传导的理解是不完整的。在这个项目中，我们将确定全长成纤维细胞生长因子受体（FGFR）的结构，使用尖端的原子分辨率方法，如低温电子显微镜和核磁共振光谱。FGFR和FGFRs的改变形式是几种类型的人类癌症以及一些发育障碍的原因，是控制诸如胚胎发育、伤口愈合和新血管生长（血管生成）的过程的原型RTK。FGFR通常通过成纤维细胞生长因子（FGF）与其细胞外基质的结合而被激活。（小区外部）区域，但在某些癌症和发育性疾病中，它们可能会发生改变，即使没有FGF结合，它们也会永久活跃。如果我们要了解FGFR和其他RTK如何正常发挥功能-例如，它们如何在静息状态下自我抑制，但随后被激活，那么细胞外和细胞内部分（例如，细胞外和细胞内部分）是必不可少的。这对于FGFR的癌症相关变体尤其如此，其中FGFR 3基因的一部分与来自另一种蛋白质TACC 3的基因的一部分融合，以产生超活化的杂合蛋白，并且还定位于细胞的不同部分。这些所谓的FGFR 3-TACC 3融合是某些类型的胶质母细胞瘤（侵袭性脑肿瘤）和一些膀胱癌的原因。在结构水平上了解超活化是如何发生的，将提高我们选择性靶向这些融合蛋白的能力，以更好地治疗那些癌症，他们是responsible.We还预计，这些疾病相关的FGFR变异异常活动可能会形成新的细胞内复合物与各种不同的蛋白质伴侣。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伴侣。为此，我们研究的另一个方面将是在实验室培养的癌细胞中使用交联质谱（XL-MS）来识别这些新的伙伴，并找出这些相互作用如何促进疾病过程。（正常和疾病改变的）FGFR结构和细胞相互作用，我们的目标是更好地了解为什么FGFR靶向药物分子在某些疾病环境中有效，而在其他疾病环境中不那么有效，以及我们如何开发更有效的药物分子。总之，我们的项目旨在解决以下问题：-通过解决完整FGFR及其癌症相关改变形式（例如FGFR-TACC融合）的结构，我们能否更好地了解细胞外信号（如生长因子结合）如何转化为激活FGFR产生的不同细胞内反应？- FGFR在正常细胞和癌细胞中形成什么样的功能复合物，它们告诉我们潜在的新治疗药物靶向策略是什么？

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