Dynein Coordination · Mechanical basis for motor protein coordination in axenomes leading to the beating of cilia and flagella

Cilia and flagella are highly conserved cell organelles that exhibit regular, serpentine beating motions. Each cilium and flagellum contains a motile organelle called an axoneme, which is comprised of an array of microtubules, dynein motor proteins, and accessory proteins. Recent studies have led to the hypothesis that intrinsic mechanical and mechanochemical properties of the dyneins provide the feedback and coordination necessary for the regular beating pattern of cilia and flagella. The objective of this project is to test this mechanical coordination hypothesis. The proposal takes an interdisciplinary approach, bringing together experiments and theory and using analytical tools from informatics, biochemistry, biomechanics, and mechanical engineering. Specifically, the proposal aims to measure the motor properties of individual molecules and small ensembles of dyneins using optical tweezers. These measurements will be used to evaluate the state of the art models of axoneme beating, confirming or rejecting the dynein coordination hypotheses on which they are based. The measured motor properties of dynein will be used to build a new model of the axoneme from the “bottom-up.” The principle advantage of this model over the existing models is that, rather than showing that a set of theoretical molecular properties can fit experimental data on whole flagella, it will specifically account for the measured molecular details of the axoneme. The ability of the “bottom up” model to predict experimentally acquired flagellar beat patterns will be compared to models from the literature. This project will be part of an increasing number of studies on the role mechanics and forces have on biology at the cell level. It will not only further our understanding of dynein coordination and flagellar motion, but also biological coordination in general, a phenomenon that has allowed for the evolution of complex organisms, but has remained largely unexplained.