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.

抽象的 机械敏感道通道的结构机制 由机械敏感通道介导的机械力感觉是一系列基本的基础 生理过程，包括听力，触摸，本体感受，渗透调节和形态发生。 功能失调的力感觉与许多疾病有关，包括耳聋，动脉粥样硬化， 慢性疼痛和癌症。小电导（MSC）的核核酸机械敏感通道保护 在低湿度下损中破裂的细菌细胞。多种类似于MSC的通道 包括细菌，真菌，藻类和植物在内的生物，形成了一个异常多样的通道 对于管理渗透压至关重要。动物中没有MSC同源物，因此 靶向病原微生物（例如细菌和真菌）中的MSC通道可能导致新的 抗菌治疗策略。当前的机械理解，主要是从研究 典型的原核通道大肠杆菌MSC仍然有限。结构，生化和生物物理 对复杂膜蛋白的分析，例如真核MSC通道和多域核酸 由于产生足够大量的大量困难，MSC同源物已被证明具有挑战性 生化稳定的蛋白质样品。我们通过最近的发展克服了这些关键障碍 在大规模的蛋白质生产以及各种MSC家族成员的结构和功能分析中 具有不同的膜拓扑和域组织。我们最近的结构和功能研究 真核通道MSL1发现了一种“扁平和膨胀”门控机制 静止状态下的非平面跨膜结构域，这让人联想到进化和 建筑无关的哺乳动物机械敏感的压电通道。这些结果导致我们的中心 假设跨膜区域中的“扁平与扩张”可能是统一的门控机制。 有了这些令人兴奋的发展，我们现在能够将结构生物学和电生理学结合到 地址机械生物学中的主要问题之一：机械敏感的通道门如何？ 具体而言，我们旨在揭示具有不同膜的多种MSC渠道的门控转变 拓扑以进一步评估这种潜在的通用门控机制。对 机制将提供关键信息，最终导致新抗菌剂的发展 与机械改变相关的广泛疾病的试剂和新治疗策略 力感觉。