Entanglement in Biology-Pierced Lassos and Deep Knots

生物学中的纠缠——刺穿的套索和深结

• 批准号: 1614407
• 负责人: Patricia Jennings
• 金额: $ 72万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1614407&HistoricalAwards=false
• 关键词: Entanglement; Biology; Pierced; Lassos; Deep

Unexpectedly, proteins can tie themselves into knots in their native folds. Since protein folding from an unstructured molecular chain into the native-state is already complex, the existence of knotted chains immediately raises the questions: how does the chain cross itself to form a knot and how does the knot affect function? The PIs discovered a class of proteins, with leptin as the founding member. This growing class now includes well over 350 protein families, spanning a huge range of fold types and including all secondary structure elements. The goal of the current project is to use a multifaceted approach to investigate how the fundamental mechanisms of knotting/unknotting/threading are initiated and relate to overall protein folding, and how the knotted functional and folding landscapes are related. One of the PIs has been involved in K-12 outreach by performing scientific experiments at local grammar schools which are greater than 50% minority students, by also helping to train children in middle school for the Science Olympiad, hosting High School students as research interns for the summer and by hosting people interested in a career in teaching in primary and secondary schools as research assistants in her laboratory. This effort will allow the PI to convey a true excitement for science to the K-12 population and she is currently in the planning stages of intensifying her K-12 outreach efforts by coordinating visits to local bilingual schools accompanied by successful minority, male and female students from UCSD that will provide role models for the local students.The simplest backbone, deep-knotted proteins are the 31 trefoil knots such as in the trefoil methyltransferase (MT) families. The PIs showed that an extended time in the denatured state is required for unknotting in these proteins. The PIs will investigate whether specific regions identified as barriers to untying in the MTs also contribute to functional regulation and ligand gating in the native states because of long-range coupling of topologically frustrated regions. The preliminary data are consistent with this hypothesis. Further exploration building upon these foundational studies will allow the PIs to investigate the interplay between the strained topology inherent in a knotted conformation and communication between functional sites. These studies will allow the PIs to describe, for the first time, the physical-chemical variables necessary to overcome the topological barrier for initiating threading as well as the role of the PL on the functional dynamics of a proteinThis project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences.

出乎意料的是，蛋白质可以在其天然折叠中将自己捆绑成结。由于蛋白质从非结构化分子链折叠到自然状态已经很复杂，打结链的存在立即提出了问题：链如何交叉形成一个结，以及这个结如何影响功能？PI发现了一类蛋白质，瘦素是其创始成员。这一不断增长的类别现在包括350多个蛋白质家族，涵盖了广泛的折叠类型，并包括所有二级结构元素。本项目的目标是使用多方面的方法来研究打结/解结/穿线的基本机制是如何启动的，以及如何与整体蛋白质折叠相关，以及打结的功能和折叠景观是如何相关的。其中一名私人助理参与了从K到12的推广活动，在当地文法学校(少数民族学生占50%以上)进行科学实验，还帮助培训中学生参加科学奥林匹克竞赛，接待高中生作为暑期研究实习生，并在她的实验室作为研究助理接待有兴趣在中小学任教的人。这一努力将使PI向K-12人群传达对科学的真正兴奋，她目前正处于规划阶段，通过协调对当地双语学校的访问，陪同来自加州大学圣迭戈分校的成功的少数族裔、男性和女性学生，将为当地学生提供榜样。最简单的骨架、深打结的蛋白质是31个三叶结，例如三叶草甲基转移酶(MT)家族。PI显示，这些蛋白质在变性状态下需要较长的时间才能解结。PI将调查在MTS中被确定为解锁障碍的特定区域是否也有助于自然状态下的功能调节和配体门控，因为拓扑受挫区域的远程耦合。初步数据与这一假设是一致的。在这些基础研究的基础上进行的进一步探索将使PI能够调查打结构象中固有的应变拓扑与功能位点之间的通信之间的相互作用。这些研究将使PI首次描述克服启动穿线的拓扑障碍所需的物理-化学变量以及PL在蛋白质功能动力学中的作用。该项目由物理学部的生命系统物理学计划和分子和细胞生物科学部的分子生物物理组共同支持。

项目成果

Pierced Lasso Topology Controls Function in Leptin

刺穿套索拓扑控制瘦素的功能

• DOI: 10.1021/acs.jpcb.6b11506
• 发表时间: 2017
• 期刊: The Journal of Physical Chemistry B
• 作者: Haglund, Ellinor;Pilko, Anna;Wollman, Roy;Jennings, Patricia Ann;Onuchic, José Nelson
• 通讯作者: Onuchic, José Nelson