Transitions to Excellence: Structural Cell Biology of Kinesin Motor Proteins

Indiana University, Bloomington IN

Investigators

Abstract

Nearly all cells in our bodies contain miniaturized cellular highways, known as the microtubule cytoskeleton, that are used as tracks for transport of material inside cells. These structures also help drive cell movement and form the machinery necessary to segregate the genetic material during cell division. Unlike the rigid cement foundation of a roadway, cellular highways are unique in that they are rigid enough to support movement of material that is a hundred times its size, and yet they are dynamic and can be reorganized in a matter of seconds. This project addresses how cellular motors both move on the cellular highways and control their reorganization, which will provide fundamental new insights into cytoskeletal regulation in cells. This project will also have broader impacts through training and mentoring of both undergraduate students and high-school students, including URM students from multiple IU sponsored programs. The study of molecular motor proteins provides an ideal learning tool for students to literally “see” science in action at the molecular scale in addition to learning about the scientific process of data collection, analysis and presentation. In addition, this project will develop a new career mentoring program for undergraduate students in two IU sponsored research programs to help students navigate career choices at an earlier stage of college and broaden their participation in STEM careers. Molecular motor proteins that walk along the microtubules are part of families of enzymes, called kinesins, that share a conserved catalytic domain used to walk along the microtubule and a non-catalytic tail domain that determines specificity of their action in cells. This project seeks to elucidate the mechanisms that control the regulation of tail binding specificity. While cell biological approaches can uncover where a motor acts, and biochemical approaches can indicate which proteins it binds to and how tightly, a detailed molecular understanding can best be achieved through structural studies that will elucidate how different motor and tail domains are organized along the microtubule lattice. Structural understanding of the microtubule has been transformed by recent advances in the field of cryo-electron microscopy. The project will utilize cryo-electron microscopy to address how motor and non-motor tail domains of a single kinesin motor interact with the microtubule and will test how a conserved regulator modulates binding of multiple motor tail domains. In addition, this project will provide collaborative training in cryo-electron microscopy for a senior level cell biologist to expand their research program through the implementation of this powerful technology. These studies will provide new insights into understanding how microtubule structure impacts both dynamics and transport properties of molecular motors. 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.