Structural Mechanism for Gating of Mechanosensitive Channels

机械敏感通道门控的结构机制

• 批准号: 10818026
• 负责人: Peng Yuan
• 金额: $ 33.23万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818026
• 关键词: Structural; Mechanism; Gating; Mechanosensitive; Channels

ABSTRACT Structural Mechanism for Gating of Mechanosensitive Channels Mechanical force sensation mediated by mechanosensitive channels underlies an array of fundamental physiological processes, including hearing, touch, proprioception, osmoregulation, and morphogenesis. Dysfunctional force sensation is associated with numerous diseases including deafness, atherosclerosis, chronic pain and cancer. The prokaryotic mechanosensitive channel of small conductance (MscS) protects bacterial cells from rupture under hypoosmotic downshock. A variety of MscS-like channels, found in many organisms including bacteria, fungi, algae, and plants, form an exceptionally diverse superfamily of channels that are crucial for management of osmotic pressure. MscS homologs are absent in animals, and thus targeting MscS channels in pathogenic microorganisms such as bacteria and fungi could lead to new antimicrobial treatment strategies. Current mechanistic understanding, primarily inferred from studies of the prototypical prokaryotic channel, E. Coli MscS, remains limited. Structural, biochemical, and biophysical analyses of complex membrane proteins such as eukaryotic MscS channels and multi-domain prokaryotic MscS homologs have proven challenging owing to major difficulties in producing sufficiently large quantities of biochemically stable protein samples. We have overcome these critical barriers through recent developments in large-scale protein production and structural and functional analyses of a variety of MscS family members with distinct membrane topologies and domain organizations. Our recent structural and functional studies of a eukaryotic channel MSL1 have uncovered a `flattening and expansion' gating mechanism stemming from a non-planar transmembrane domain at the resting state, which is reminiscent of the evolutionarily and architecturally unrelated mammalian mechanosensitive Piezo channels. These results lead to our central hypothesis that `flattening and expansion' in the transmembrane region may be a unifying gating mechanism. With these exciting developments, we are now able to combine structural biology and electrophysiology to address one of the central questions in mechanobiology: how do mechanosensitive channels gate? Specifically, we aim to reveal gating transitions of a diverse set of MscS channels with distinct membrane topologies to further evaluate this potentially universal gating mechanism. Detailed understanding of the mechanisms will provide critical information that will ultimately lead to development of new antimicrobial reagents and new treatment strategies for a broad spectrum of diseases associated with altered mechanical force sensation.

摘要 机械敏感通道门控的结构机制 由机械敏感通道介导的机械力感觉是一系列基本的 生理过程，包括听觉、触觉、本体感觉、触觉调节和形态发生。 力觉功能障碍与许多疾病有关，包括耳聋、动脉粥样硬化， 慢性疼痛和癌症。原核小电导机械敏感通道（MscS） 细菌细胞在低渗下休克下破裂。多种类似MSC的通道，在许多 包括细菌、真菌、藻类和植物在内的生物体形成了异常多样的通道超家族 对渗透压的控制至关重要。mscS同源物在动物中不存在，因此 针对病原微生物如细菌和真菌中的MscS通道， 抗菌治疗策略。目前的机械理解，主要是从研究推断的 原型原核通道E.大肠杆菌MscS，仍然有限。结构、生物化学和生物物理 分析复杂的膜蛋白，如真核细胞MscS通道和多结构域原核细胞 由于在生产足够大量的MscS同系物方面存在重大困难，因此MscS同系物已被证明具有挑战性。 生化稳定的蛋白质样本我们通过最近的事态发展克服了这些关键障碍 在大规模蛋白质生产和各种MscS家族成员的结构和功能分析中， 具有不同的膜拓扑结构和域组织。我们最近的结构和功能研究， 真核细胞通道MSL1揭示了一种“扁平化和扩展”门控机制， 非平面跨膜结构域在静止状态，这是令人想起的进化， 结构无关的哺乳动物机械敏感压电通道。这些结果导致我们的中央 假设跨膜区的“扁平化和扩张”可能是一种统一的门控机制。 有了这些令人兴奋的发展，我们现在能够将联合收割机结构生物学和电生理学结合起来， 解决机械生物学中的一个中心问题：机械敏感通道如何门控？ 具体来说，我们的目标是揭示不同的MscS通道的门控转换， 拓扑，以进一步评估这种潜在的通用门控机制。详细了解 机制将提供关键信息，最终导致开发新的抗菌剂， 用于与机械改变相关的广谱疾病的试剂和新的治疗策略 力觉