The Molecular Basis for Myosin-10 Regulation - PROJECT SUMMARY/ABSTRACT A critical function for all living organisms is the ability to move when needed. These movements–intracellular trafficking, cell division, muscle contraction, and cell motility–are driven by molecular machines that exert an amazing amount of force considering that they are only a few nanometers across. Given the variety of motor proteins in the cell, a key question is how motors cooperate and compete while moving cargoes and applying forces. An emerging paradigm is the notion of specialized motors, or motors that are fine-tuned to perform a specific function. Despite the importance of these motor proteins, relatively little is known about their individual adaptations and how these relate to the motility patterns found in the cell. This work focuses on myosin-10 and its unique ability to navigate to a specific location in the cell. Myosin-10 delivers essential cargoes such as integrins, cadherins and netrin receptors to filopodia at the leading edge of the cell. This transport function plays a pivotal role in migrating cells, both in normal developmental biology and in metastasizing tumor cells. To navigate the cell, myosin-10 walks along multiple filaments in the fascin-actin bundle found at the core of the filopodium, and effectively ignores other actin filaments in the rest of the cell. The proposed work will study how ligand binding, myosin quaternary structure, and actin filament architecture all tune myosin-10 motility. The approach will integrate structural biology techniques applied to full-length myosin-10, coupled with a comprehensive and systematic investigation of the ligands that lead to full activation and processive motility. This proposal will test the hypothesis that myosin-10 is regulated by head-to-tail autoinhibitory interactions that are relieved by phosphorylation and, potentially, cargo binding. Completion of this study will yield a molecular mechanism for cytoskeletal motor protein navigation in the cell. It will further define the general principles that determine how all types of cytoskeletal motors engage cargo, activate, and navigate. Motor protein activation and navigation is a process of fundamental biological importance but is poorly understood. This work will direct future efforts to understand and control motility in multiple contexts.
