Dynamic Mechanisms of Membrane Channel Gating by CryoEM

CryoEM 膜通道门控的动态机制

• 批准号: 10687015
• 负责人: Stephen Loen Reichow
• 金额: $ 43.12万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687015
• 关键词: Address; Architecture; Arrhythmia; Biological Phenomena; Biophysics; Blindness; Brain; Cell Communication; Cells; Chemicals; Communication; Complex; Computer Models; Coupled; Cryoelectron Microscopy; Development; Disease; Environment; Gap Junctions; Hand; Heart; Imaging technology; Investigation; Ion Channel; Knowledge; Light; Lipids; Malignant Neoplasms; Mediator; Medical; Membrane Proteins; Methods; Molecular; Pathway interactions; Physiological; Protein Biochemistry; Protein Structure Databases; Proteins; Regulation; Research; Resolution; Signal Transduction; Smell Perception; Stroke; Structure; Taste Perception; Touch sensation; deafness; high resolution imaging; in situ imaging; intercellular communication; pharmacologic; sound; targeted treatment; tool

Project Summary Pore-forming membrane channels are central mediators of many complex biological phenomena; such as synchronizing the contraction of our heart and electro-chemical signals in our brain, and detecting light, sound, touch, taste and smells of the world around us. This ability is dependent upon dynamic mechanism used to spatially and temporally modulate their cellular activity. Our research group is focused on understanding how these types of phenomena are choreographed by remarkably complex strategies of cell-to-cell communication, through the gap junctions. We aim to develop a molecular and atomic-level of mechanistic understanding of how gap junctions coordinate inter-cellular communication. To achieve this level of detail, we are combining the unique power of electron cryo-microscopy (CryoEM), together with computational modeling and targeted biophysical and functional studies to address several fundamental questions, such as: i) How do the gap junctions selectively control the flow of chemical information between cells? ii) How are their activities allosterically modulated by physiological signals and pharmacological agents? iii) How gap junction assembly, structure and function is coupled with the local lipid/cellular environment? Despite their physiological and medical relevance, membrane proteins still only represent ~4% of the protein structure database. However, recent advances in the field of high-resolution CryoEM, coupled with advancements in membrane protein biochemistry and in situ imaging technologies, are beginning to revolutionize the way we structurally characterize these proteins. With these tools in hand, we are addressing several key questions about gap junction assembly, selectivity and regulation. The results of our investigations are expected to provide an architectural framework and the mechanistic knowledge required for the rational development of targeted therapies against a range of gap junction related diseases, such as blindness, deafness, arrhythmia, stroke and cancers.

项目摘要 形成孔隙的膜通道是许多复杂生物学现象的中心介体。例如 同步我们大脑中心脏和电化学信号的收缩，并检测光，声音， 我们周围世界的触摸，味道和气味。这种能力取决于曾经的动态机制 在空间和时间上调节其细胞活性。我们的研究小组专注于了解如何 这些类型的现象是通过细胞到细胞通信的非常复杂的策略来编排的， 通过间隙连接。我们旨在建立对机械理解的分子和原子级别的理解 间隙连接如何协调细胞间通信。为了达到这个细节，我们正在结合 电子冷冻微镜（Cryoem）的独特功能，以及计算建模和目标 生物物理和功能研究以解决几个基本问​​题，例如：i）差距如何 连接选择性控制细胞之间的化学信息流？ ii）他们的活动如何 由生理信号和药理学剂进行变构调节？ iii）间隙连接组件如何 结构和功能与局部脂质/细胞环境结合在一起？尽管它们的生理和 医学相关性，膜蛋白仍然仅占蛋白质结构数据库的约4％。然而， 高分辨率冷冻领域的最新进展，再加上膜蛋白的进步 生物化学和原位成像技术开始彻底改变我们在结构上的方式 表征这些蛋白质。借助这些工具，我们正在解决有关差距的几个关键问题 连接组装，选择性和调节。我们的调查结果预计将提供 建筑框架和有针对性的合理发展所需的机械知识 针对一系列相关疾病的疗法，例如失明，耳聋，心律不齐，中风 和癌症。

项目成果

The α-crystallin chaperones undergo a quasi-ordered co-aggregation process in response to saturating client interaction.

α-晶状体蛋白伴侣经历准有序共聚集过程以响应饱和客户交互。

• DOI: 10.1101/2023.08.15.553435
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Miller,AdamP;O'Neill,SusanE;Lampi,KirstenJ;Reichow,SteveL
• 通讯作者: Reichow,SteveL

Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly.

• DOI: 10.1016/j.celrep.2021.110168
• 发表时间: 2021-12-28
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Buonarati OR;Miller AP;Coultrap SJ;Bayer KU;Reichow SL
• 通讯作者: Reichow SL

Multivalency regulates activity in an intrinsically disordered transcription factor.

• DOI: 10.7554/elife.36258
• 发表时间: 2018-05-01
• 期刊: eLife
• 影响因子: 7.7
• 作者: Clark S;Myers JB;King A;Fiala R;Novacek J;Pearce G;Heierhorst J;Reichow SL;Barbar EJ
• 通讯作者: Barbar EJ