1. <acronym id="wsdrq"><legend id="wsdrq"><blockquote id="wsdrq"></blockquote></legend></acronym>

    2. <code id="wsdrq"><ol id="wsdrq"></ol></code>
      <meter id="wsdrq"><ol id="wsdrq"><span id="wsdrq"></span></ol></meter>
    3. <code id="wsdrq"></code>
    4. <output id="wsdrq"><video id="wsdrq"></video></output>

      Protein clumps: The hnRNPA2 protein forms liquid droplets in a test tube as seen by light microscopy. These structures let the researchers test how disease mutations and functional modifications change the behavior of the proteins with atomistic detail. Veronica Ryan/Brown University

      Research reveals atomic-level changes in ALS-linked protein

      A new study details the minute changes—down to the level of individual atoms—that cause a particular protein to form cell-damaging clumps associated with ALS and other diseases.

      PROVIDENCE, R.I. [Brown University] — For the first time, researchers have described atom-by-atom changes in a family of proteins linked to amyotrophic lateral sclerosis (ALS), a group of brain disorders known as frontotemporal dementia and degenerative diseases of muscle and bone. Their findings appear in the journal Molecular Cell.

      The long-term goal of the research is to target this cellular pathway with a drug or other therapy to prevent these diseases, said the study’s senior author, Nicolas Fawzi of Brown University. “There is currently no therapy or cure for ALS and frontotemporal dementia. We are pursuing new hypotheses and angles to fight these illnesses.”

      Many proteins connected with these diseases contain “low-complexity” domains or pieces. Compared to a cell’s best-understood proteins, which are ordered and static in structure, low-complexity domains are squirmy and disordered. Instead of a rigid shape, these pieces of protein are flexible and float inside cells until cued into action.

      In non-disease situations, low-complexity domains help proteins perform healthy functions, including assembling into liquid-like droplets, where important cellular processes, such as RNA processing, take place.

      When low-complexity domains go awry, as in disease, they transform into inclusions, intractable and accumulating knots or clumps. In certain cancers, low-complexity domains are improperly attached to other proteins that may then incorrectly form droplets in cellular locations, leading to misregulated expression of genes, Fawzi said.

      “We’re trying to understand why they change behavior and aggregate, and how we can disrupt those processes,” he said.

      In the study, the researchers describe the microscopic physical interactions and chemical changes of proteins associated with several cellular functions, including disease forms, and how still-healthy cells could try to temper it.

      “We show how small chemical changes — involving only a few atoms — lead to big changes in assembly and disease-associated aggregation,” Fawzi said. “These interactions are more dynamic and less specific than previously thought. A molecule does not take just one shape and bind to one shape but a molecule is flexible and interacts in flexible ways.”

      Cells divide up their function within distinct cellular structures called organelles, which traditionally thought of as being encased by membranes. The researchers studied a protein, called hnRNPA2, which is mutated in disease. The protein collects in membrane-less organelles, where it may use its low-complexity domain to stick together, much in the way that water collects into droplets on the outside of a cold soda bottle on a humid summer day. Until the publication of this study, several mechanistic details of how the low-complexity domain of hnRNPA2 worked and how it changed into aggregates in disease were unknown.?

      Using nuclear magnetic resonance (NMR) spectroscopy, computer simulations and microscopy, the researchers showed how disease mutations and arginine methylation, a functional modification common to a large family of proteins with low-complexity domains, altered the formation of the liquid droplets and their conversion to solid-like states in disease.

      These findings explain several threads of research conducted over the last 20 years on the role of hnRNP family proteins in neuron function and neurodegeneration, said Fawzi, who is an assistant professor in the Department of Molecular Pharmacology, Physiology and Biotechnology.

      Previously Fawzi and colleagues described the structure and biophysics of a related protein, how ALS-associated genetic flaws interfered with its proper function and behavior of another member of the protein family, causing it to aggregate. A separate study revealed a possible means of ?preventing those clumps from forming.

      “Because these low-complexity domains are too flexible to be directly targeted by standard drugs, finding out how cells use and tame these domains is a potential route to stopping their unwanted assembly in disease,” Fawzi says.

      Grants from the National Institute of General Medical Sciences, ALS Association and Judith and Jean Pape Adams Charitable Foundation funded this latest study.

      The study’s lead author is Brown graduate student Veronica H. Ryan. Other authors include Charlene V. Chabata, Rute Silva, Alexander E. Conicella, Joshua Amaya and Kathleen A. Burke from Brown University, and Gregory L. Dignon, Gül H. Zerze, and Jeetain Mittal from Lehigh University.

      惠农| 吐鲁番| 东丰| 佛爷顶| 昌宁| 察哈尔右翼中旗| 朱日和| 长顺| 元谋| 双辽| 平潭海峡大桥| 长春| 浦口| 砀山| 东营| 南沙岛| 新巴尔虎右旗| 荣成| 鄢陵| 滕州| 金华| 新竹市| 曲阳| 宜川| 榆树| 宣城| 峡江| 儋州| 交口| 吕梁| 和龙| 乌兰乌苏| 稻城| 诸暨| 彰武| 中心站| 姜堰| 玉山| 息县| 斗门| 大名| 墨江| 勐腊| 防城| 方城| 鹤山| 略阳| 福清| 雅江| 桂林农试站| 潼关| 太原北郊| 莎车| 德保| 卓尼| 宁县| 岚皋| 西盟| 海口| 硕龙| 鞍山| 威远| 滦平| 杭锦后旗| 陵县| 科尔沁左翼后旗| 彭阳| 盈江| 大宁| 鲁甸| 茶卡| 井陉| 天柱| 华池| 萧山| 雄县| 新泰| 尉犁| 滨海| 佛冈| 阆中| 安达| 北川| 长泰| 开江| 海阳| 海口| 金沙| 上杭| 郯城| 福鼎| 深州| 拐子湖| 五道梁| 松原| 白云| 建宁| 志丹| 辉南| 慈利| 达坂城| 遵义县| 普兰店| 常州| 镇沅| 舞钢| 苍南| 资兴| 舒城| 资源| 麻阳| 珲春| 寻乌| 宁都| 宁强| 东乡| 曹县| 新洲| 乌兰浩特| 闵行| 汾西| 高力板| 长汀| 天镇| 南昌县| 甘孜| 武川| 定海| 黄龙| 察布查尔| 麦盖提| 兰坪| 晋宁| 献县| 沐川| 夏县| 代县| 宁南| 察隅| 木兰| 江门| 贵阳| 宁河| 天山大西沟| 白玉| 芒康| 闽侯| 阿克陶| 大佘太| 益阳| 马坡岭| 海南| 密云上甸子| 铁卜加寺| 徐水| 柳林| 阿瓦提| 云和| 尼木| 滦南| 故城| 大埔| 建德| 九台| 城固| 南澳| 册亨| 温泉| 云龙| 博罗| 顺平| 黔江| 合浦| 古丈| 察哈尔右翼中旗| 深州| 宜宾县| 什邡| 遂川| 察哈尔右翼中旗| 巴音布鲁克| 永定| 屏边| 加格达奇| 安宁| 宁津| 索伦| 临沧| 涟源| 都安| 普宁| 武隆| 界首| 乌鞘岭| 石泉| 汝南| 荣县| 克什克腾旗| 平潭| 泗水| 南漳| 介休| 伊和郭勒| 长葛| 洪家| 乐东| 阳泉| 连山| 绛县| 红安| 夹江| 吉木乃| 上饶县| 渝北| 定襄| 绥宁| 伊吾| 吴县| 太康| 秭归| 黑山| 通渭| 永靖| 二连浩特| 徐家汇| 雅江| 四子王旗| 崇武| 东兴| 威信| 清水河| 扶绥| 峨山| 沧州| 北海| 朝克乌拉| 高碑店| 襄阳| 鄢陵| 大佘太| 腾冲| 理县| 勐腊| 洋县| 德清| 赤城| 六库| 东吉屿| 民乐| 吉首| 普安| 西充| 新建| 江浦| 巫溪| 万源| 鸡东| 阿鲁科尔沁旗| 曲江| 威海| 金秀| 泗阳| 安远| 循化| 天山大西沟| 忠县| 邛崃| 科尔沁左翼后旗| 石景山| 薛城| 清涧| 化德| 肇源| 衡山| 宿迁| 株洲| 溧阳| 吴桥| 遂宁| 兰坪| 西连岛| 黄山站| 郑州| 万盛| 富阳| 隆德| 内邱| 秦安| 仙游| 小灶火| 镇远| 康平| 锦州| 长垣| 宁洱| 阿克陶| 清水河| 武山| 宁都| 柯坪| 公安| 清徐| 周宁| 永济| 合作| 温州| 安泽| 昭平| 滕州| 靖西| 灵石| 河口| 淇县| 深圳| 耿马| 祁县| 阿合奇| 故城| ??| 南木林| 范县| 剑阁| 定西| 将乐| 宜都| 通山| 普兰| 大同| 洪家| 铜锣湾| 永善| 河卡| 多伦| 同江| 桂林农试站| 沂南| 澳门| 郸城| 藤县| 巫溪| 锦屏| 江永| 肇庆| 扬中| 合作| 宁晋| 多伦| 宁晋| 惠农| 从江| 叶城| 玛沁| 赤城| 尖扎| 井冈山| 九龙| 永署礁| 南陵| 汉沽| 宁海| 铁岭| 巫溪| 威宁| 新宁| 上高| 犍为| 闽清| 深泽| 日照| 魏山| 汤原| 河源| 莱州| 蒲江| 奉新| 武穴| 遵义| 新田| 江宁| 正镶白旗| 饶河| 津南| 苍溪| 广南| 阿瓦提| 余江| 千阳| 龙门| 大兴安岭| 凯里| 融水| 平罗| 佳县| 余庆| 嵩明| 华池| 天长| 册亨| 襄城| 河津