Identifying the molecular mechanisms that mediate cell membrane repair

识别介导细胞膜修复的分子机制

• 批准号: 1905091
• 负责人: Joe Baio
• 金额: $ 45万
• 依托单位: Oregon State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1905091&HistoricalAwards=false
• 关键词: Identifying; molecular; mechanisms; mediate; cell

The protein dysferlin initiates and controls the process of repairing damage to the cell membranes of muscles during physical movement. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding a team led by Professor Joe Baio from Oregon State University to investigate the key chemical interactions that dictate dysferlin repairs and manipulate biological membranes. Certain types of muscular dystrophy, including Limb-girdle muscular dystrophy type 2B and Miyoshi distal myopathy muscular dystrophy are connected to mutations within the dysferlin protein. This project specifically studies how the interactions of dysferlin with components of the cell membrane start the repair process. Results from this research help unlock answers to how chemical miscues lead to downstream musculoskeletal diseases. Professor Baio plans to integrate this project into an outreach program designed to increase the representation of Native Americans in STEM disciplines by providing training opportunities for both Native students and instructors from a local American Indian school. The overall goal of this project is to establish the chemical principles that dictate how key proteins repair and manipulate biological membranes. When muscle sarcolemma is damaged, calcium leaks into the cell and exposure to calcium ions trigger a binding event between dysferlin's outer domain and an intracellular lipid vesicle. It has been postulated that following lipid binding, dysferlin then directs this liposome towards the damaged portion of the membrane, where it fuses and patches the damaged membrane. In this project, sum frequency vibrational spectroscopic approaches is applied to resolve the chemical interactions between dysferlin and phospholipids that trigger the initial lipid binding step and guide vesicle shuttling. This approach provides the geometry and positions of important atoms and protein structures at the dysferlin-plasma membrane interface. These approaches are then repeated for dysferlin variants associated with dysferlinopathies demonstrating how mutations within the protein contribute to a failure of this mechanism. Finally, this experimental work also provides crucial evidence that sum frequency vibrational spectroscopy-based approaches can potentially be applied to the dissection of any complex membrane protein-lipid interaction. In addition, Professor Baio works with teachers and students from a local Native American boarding school and provides them with opportunities to engage in research during the summers.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.

失铁蛋白启动并控制着在运动过程中修复肌肉细胞膜损伤的过程。通过这一奖项，化学部的生命过程化学项目资助了一个由俄勒冈州立大学的Joe Baio教授领导的团队，该团队研究决定迪尔费林修复和操纵生物膜的关键化学相互作用。某些类型的肌营养不良症，包括肢体带状2B型肌营养不良症和Miyoshi远端肌病肌营养不良症与dyferlin蛋白内的突变有关。这个项目专门研究去铁蛋白与细胞膜成分的相互作用如何启动修复过程。这项研究的结果有助于揭开化学失误如何导致下游肌肉骨骼疾病的答案。拜约教授计划将这一项目整合到一个外联项目中，旨在通过为土著学生和当地美国印第安人学校的教师提供培训机会，增加美洲原住民在STEM学科中的代表性。这个项目的总体目标是建立决定关键蛋白质如何修复和操纵生物膜的化学原理。当肌肉肌膜受损时，钙离子泄漏到细胞内，并暴露在钙离子中，触发dyferlin的外区与细胞内脂泡之间的结合事件。据推测，在脂质结合之后，去铁蛋白将脂质体引导到膜的受损部分，在那里它融合并修补受损的膜。在这个项目中，和频振动光谱方法被用来解决去铁蛋白和磷脂之间的化学相互作用，这些相互作用触发了初始的脂质结合步骤，并引导囊泡穿梭。这种方法提供了重要的原子和蛋白质结构在干扰素-质膜界面上的几何形状和位置。然后，这些方法被重复用于与铁代谢障碍相关的脱铁蛋白变异，展示了蛋白质内的突变如何导致这一机制的失败。最后，这项实验工作还提供了关键证据，证明基于和频振动光谱的方法可以潜在地应用于剖析任何复杂的膜蛋白-脂质相互作用。此外，拜奥教授与当地一所美洲原住民寄宿学校的教师和学生一起工作，并在暑期为他们提供从事研究的机会。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Calcium Sensitive Allostery Regulates the PI(4,5)P2 Binding Site of the Dysferlin C2A Domain

钙敏感变构调节 Dysferlin C2A 结构域的 PI(4,5)P2 结合位点

• DOI: 10.1101/2021.02.10.430549
• 发表时间: 2021
• 期刊: bioRxiv
• 作者: Otto, Shauna C;Reardon, Patrick N;Kumar, Tanushri M;Kuykendall, Chapman J;Johnson, Colin P.
• 通讯作者: Johnson, Colin P.

Evidence that gecko setae are coated with an ordered nanometre-thin lipid film

• DOI: 10.1098/rsbl.2022.0093
• 发表时间: 2022-07
• 期刊: Biology Letters
• 影响因子: 3.3
• 作者: M. H. Rasmussen;Katinka Rønnow Holler;J. Baio;C. Jaye;D. Fischer;S. Gorb;T. Weidner

Model Asphaltenes Adsorbed onto Methyl- and COOH-Terminated SAMs on Gold

吸附在金上甲基和 COOH 封端 SAM 上的沥青质模型

• DOI: 10.1021/acs.langmuir.1c01338
• 发表时间: 2021
• 期刊: Langmuir
• 影响因子: 3.9
• 作者: Golbek, Thaddeus W.;Faase, Ryan A.;Rasmussen, Mette H.;Tykwinski, Rik R.;Stryker, Jeffrey M.;Ivar Andersen, Simon;Baio, Joe E.;Weidner, Tobias
• 通讯作者: Weidner, Tobias

Structure of Keratins in Adhesive Gecko Setae Determined by Near-Edge X-ray Absorption Fine Structure Spectromicroscopy

• DOI: 10.1021/acs.jpclett.2c00004
• 发表时间: 2022-03-10
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY LETTERS
• 影响因子: 5.7
• 作者: Holler, Katinka Ronnow;Rasmussen, Mette A.;Weidner, Tobias
• 通讯作者: Weidner, Tobias

Orientation of the Dysferlin C2A Domain is Responsive to the Composition of Lipid Membranes

• DOI: 10.1021/acs.jpcb.2c06716
• 发表时间: 2023-01-06
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY B
• 影响因子: 3.3
• 作者: Carpenter，Andrew P.;Khuu，Patricia;Baio，Joe E.
• 通讯作者: Baio，Joe E.