CAREER: The molecular interplay between integrin adhesion, allostery and shape-shifting

职业：整合素粘附、变构和变形之间的分子相互作用

• 批准号: 2239492
• 负责人: Mehmet Sen
• 金额: $ 66.34万
• 依托单位: University of Houston
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2239492&HistoricalAwards=false
• 关键词: CAREER; molecular; interplay; between; integrin

Adhesion molecules are proteins on cell surfaces that facilitate cellular adhesion, migration, and interactions with the external environment. These adhesion molecules, specifically called integrins, share an almost identical topology and are highly proficient, precise, and specific at ambient conditions. Moreover, they are highly evolvable and easily adapt to new mechanisms. Integrin α/β heterodimers are expressed in all animals (from sponges to vertebrates), bind different ligands, and at least one integrin is expressed in each human cell type. Exactly how each integrin has been diverged to play a particular role is largely unknown due to the lack of quantitative studies characterizing their structural changes and adhesion properties on cell surfaces. This research will focus on defining the structural and adhesive properties of a white blood cell-specific integrin receptor, which is only present in vertebrate animals. This research will employ biophysics, biochemistry, structural biology, and chemistry approaches to relate the changes in this leukocyte integrin’s conformation and adhesion. The biotechnology summer workshop, designed for K–12 STEM students and undergraduates who are training to be future STEM teachers, will provide insight into the fundamental understanding of biomolecular structures and how alterations in these structures are related to protein function. Leukocyte integrins allosterically communicate mechanical and biochemical information and regulate many cellular events that involve leukocyte migration, diapedesis towards the site of tissue damage or infection, and phagocytosis. How do leukocyte integrins achieve such diverse functions while allosterically regulating their affinities and structures? The overarching objective of this proposal is to quantify its conformational kinetics that are thermodynamically equilibrated between different integrin conformations, measure the occupancy and intrinsic affinities, and determine cryo-EM structures of each leukocyte integrin conformational state. Quantitative characterization of the integrin dynamic allostery events would greatly advance our understanding of integrin biology, open new doors to elaborate integrin evolutionary adaptations to different functions and would be powerful in enabling both more efficient protein engineering with multiple functional outputs and effector design. This project is funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

粘附分子是细胞表面上的蛋白质，可促进细胞粘合剂，迁移和与外部环境的相互作用。这些粘合剂分子，特别称为整联蛋白，具有几乎相同的拓扑结构，并且在环境条件下高度熟练，精确且具有特异性。此外，它们具有高度可转化的，并且很容易适应新的机制。整联蛋白α/β异二聚体在所有动物（从赞助者到脊椎动物），结合不同的配体中均表达，并且在每种人细胞类型中至少表达一个整合素。由于缺乏定量研究表征其结构变化和细胞表面上的粘合特性，因此在很大程度上未知每个整合素以发挥特定作用。这项研究将着重于定义白细胞特异性整合素受体的结构和粘合性特性，该素受体仅存在于脊椎动物中。这项研究将就业生物物理学，生物化学，结构生物学和化学方法，以联系该白细胞整合素整合素的会议和依从性的变化。为培训成为未来STEM教师的K – 12 STEM学生和本科生设计的生物技术夏季研讨会将提供对对生物分子结构的基本理解以及这些结构的改变如何与蛋白质功能相关的基本理解。白细胞整联蛋白变构通信机械和生化信息，并调节许多涉及白细胞迁移，向组织损伤或感染部位的脉络的细胞事件以及吞噬作用。白细胞整合素如何在变构控制其亲和力和结构的同时，如何实现此类潜水功能？该提案的总体目的是量化其构象动力学，这些动力学在不同的整合素构象，测量占用和内在亲和力之间是热力学等效的，并确定每个白细胞整合蛋白会议状态的冷冻EM结构。整联蛋白动态变构事件的定量表征将大大提高我们对整联蛋白生物学的理解，开放新的大门，以详细说明整联蛋白的进化适应不同功能，并且在启用具有多个功能输出的更有效的蛋白质工程方面将具有强大的功能。该项目由分子和细胞生物科学划分的分子生物物理学群集资助。该奖项反映了NSF的法定任务，并使用基金会的智力优点和更广泛的影响审查标准，通过评估来诚实地支持。