CAREER: Research and Education in the Structure and Function of Intramembrane Aspartyl Proteases

智力优势：在所有测序的基因组中，近三分之一编码完整的膜蛋白，这些蛋白参与关键和多样化的细胞功能，如催化、主动和被动运输以及信号转导。尽管膜蛋白在生物学上很重要，但膜蛋白的结构特征远远落后于可溶性蛋白。作为这一职业项目的一部分，将对一种特定酶(信号肽多肽酶)的结构和功能进行详细研究，该酶在脂膜范围内完成多肽水解化学。学生将确定它的三维结构，并开发直接的分析方法来测量酶的活性。此外，作为追求高分辨率分子结构的一部分，将开发促进膜蛋白结晶的新技术。晶体生长是膜蛋白结构测定中的主要限速步骤。作为这一建议的一部分而开发的方法将适用于其他膜蛋白的研究。更广泛的影响：该计划更广泛影响的一个核心方面是教育、培训和多样化未来一代科学家。除了为佐治亚理工学院本科生和研究生提供辅导活动和研究培训外，这个职业项目还包括与佐治亚州富尔顿县的西湖高中合作。高中生物教师PI和佐治亚理工学院生物化学专业的本科生将合作开发两个基于发现的模块，用于高级高中生物课程。这些模块结合了蛋白质科学、艺术和计算机，将在互联网上免费提供给所有教育工作者。老师和高中生还将在PI的实验室进行暑期研究，然后在学校和科学博览会上以海报和口头演示的形式展示他们的结果。

Intellectual Merit: Nearly one-third of all sequenced genomes encode integral membrane proteins, which are involved in critical and diverse cellular functions such as catalysis, active and passive transport, and signal transduction. In spite of their importance in biology, the structural characterization of membrane proteins lags considerably behind that of soluble proteins. As part of this CAREER project, a detailed study of the structure and function of a particular enzyme (signal peptide peptidase) that accomplishes peptide hydrolysis chemistry within the confines of the lipid membrane, will be undertaken. Students will determine its three dimensional structure and develop straightforward assays to measure enzymatic activity. In addition, as part of the pursuit of a high-resolution molecular structure, new techniques to facilitate the crystallization of membrane proteins will be developed. Crystal growth is a major rate-limiting step in membrane protein structure determination. The methods developed as part of this proposal will be applicable to the study of other membrane proteins. Broader Impact: A central aspect of the broader impact of the program is educating, training, and diversifying the future generation of scientists. In addition to mentoring activities and research training for Georgia Tech undergraduate and graduate students, this CAREER project includes a partnership with Westlake High School in Fulton County, Georgia. The PI, a high school biology teacher, and selected Georgia Tech undergraduate Biochemistry majors will collaborate to develop two discovery-based modules for an advanced high school biology course. These modules combine protein science, art and computers, and will be freely available on the internet for all educators. The teacher and high school students will also conduct summer research in the PI's laboratory, and then showcase their results as poster and oral presentations in their school and at science fairs.