Dissecting the Molecular Mechanism of Intraflagellar Transport Motors

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The 30 trillion cells that make up the human body fall into ~200 major types. Virtually all of these cell types grow an antenna-like structure called the cilium, which projects from the cell surface into the environment. Distantly related organisms such as protozoa and green algae also possess cilia, suggesting that they are ancient organelles that pre-date the last common ancestor of all eukaryotes. Cilia serve vital sensory roles, detecting and processing environmental stimuli such as light, olfactants, morphogens and fluid flow. A subset of cilia actively beat with a wave-like motion to generate cell propulsion, for example in sperm cells, or movement of fluid over the epithelia lining the airways and oviduct. Defects in the architecture and composition of cilia cause a plethora of disorders collectively known as ciliopathies. Hence, deciphering the mechanisms by which cilia are assembled and function is fundamental to understanding a wide array of biological processes and the molecular basis of disease states. We are particularly interested in the central mechanism underpinning cilia formation and function. This constitutes a transport system that moves building blocks from the cytoplasm to the tip the cilium and returns products to the cell body. It is powered by two types of ATP-fueled motor protein, which move in opposite directions along the cilium. We wish to uncover the unique mechanisms through which the motor proteins generate force and movement, coordinate round trips of transportation, and avoid colliding with each other as they traverse the cilium. To achieve this, we will use new tools to produce and manipulate the motors for detailed study.