Entanglement in Biology-Pierced Lassos and Deep Knots

出乎意料的是，蛋白质可以在它们的天然折叠中将自己打结。由于蛋白质从非结构化的分子链折叠成天然状态已经很复杂，打结链的存在立即提出了问题：链如何交叉形成结，结如何影响功能？PI发现了一类蛋白质，瘦素是创始成员。这个不断增长的类别现在包括超过350个蛋白质家族，跨越了巨大的折叠类型范围，包括所有的二级结构元件。当前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，并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PI通过在当地文法学校进行科学实验参与K-12外联活动，这些学校的少数民族学生超过50%，还帮助培训中学学生参加科学奥林匹克竞赛，接待高中学生作为夏季研究实习生，并接待有兴趣从事中小学教学职业的人作为她实验室的研究助理。这一努力将使PI能够向K-12人口传达对科学的真正兴奋，她目前正在计划加强K-12的推广工作，通过协调访问当地双语学校，由UCSD成功的少数民族，男性和女性学生陪同，为当地学生提供榜样。最简单的骨干，深结蛋白质是31个三叶结，例如三叶甲基转移酶（MT）家族中的三叶结。PI显示，这些蛋白质中的解结需要延长的变性状态时间。PI将研究确定为MT中解绑障碍的特定区域是否也有助于天然状态下的功能调节和配体门控，因为拓扑学上受抑区域的长程偶联。初步数据与这一假设一致。在这些基础研究的基础上进行进一步探索，将使PI能够研究打结构象中固有的应变拓扑结构与功能位点之间的通信之间的相互作用。这些研究将允许PI描述，第一次，物理化学变量必须克服的拓扑障碍，启动线程以及PL的作用上的功能动力学的蛋白质。该项目正在共同支持的物理学的生活系统程序在物理学和分子生物物理集群在分子和细胞生物科学部门。

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.