Myosin superfamily consists of various actin-based motors involved in a number of cellular processes. Myosin members share conserved catalytic motor head, but have distinct functional domains presented in the tail regions. These specific myosin tails, responsible for their individual cellular function, have not been characterized in detail. In order to fulfill our knowledge on how different myosins achieve their distinct functions, this thesis work took myosin X as an example and focused on systematic structural and functional characterizations of the tail domains of this specific unconventional myosin.

Myosin X is critical for the formation of filopodial structures in various tissues of mammals, and therefore is essential for numerous developmental functions such as neuronal...[ Read more ]

Myosin superfamily consists of various actin-based motors involved in a number of cellular processes. Myosin members share conserved catalytic motor head, but have distinct functional domains presented in the tail regions. These specific myosin tails, responsible for their individual cellular function, have not been characterized in detail. In order to fulfill our knowledge on how different myosins achieve their distinct functions, this thesis work took myosin X as an example and focused on systematic structural and functional characterizations of the tail domains of this specific unconventional myosin.

Myosin X is critical for the formation of filopodial structures in various tissues of mammals, and therefore is essential for numerous developmental functions such as neuronal network formation and blood vessel genesis. Myosin X contains a motor head, a coiled coil neck and a tail region composed of three PH domains and a MyTH4-FERM supramodule. Structural and biochemical data showed that the coiled coil region forms an antiparallel dimer and enables myosin X to assume unique walking property on actin filaments. It was further shown that this unexpected antiparallel-CC is required for myosin X to walk on both single and bundled actin filaments as well as to induce filopodia formation. In the myosin X tail, three consecutive PH domains and the MyTH4-FERM supramodule bind to their targets each in a unique manner. As showed in Chapter 4, PH1_N-PH2-PH1_C tandem, together with PH3, allows myosin X to bind to PI(3,4,5)P₃ containing membrane with high specificity and cooperativity. This PH123 tandem associates with specific membrane region and acts as an acute sensor in response to PI3K activation. Chapter 5 describes the structure of the myosin X MyTH4-FERM tandem in complex with the cytoplasmic tail of the axon guidance receptor DCC. It is showed that the MyTH4-FERM tandem functions as a supramodule for target recognition.

The data described in this thesis work reveal that the tail domain of myosin X can integrate lipid kinase and protein receptor signals via its PH domains and MyTH4-FERM tandem, respectively. The unique antiparallel coiled coil allows the motor to move processively on both bundled and unbundled actin filaments with long distances. Therefore, the tail domain of myosin X accounts for many unique functions of motor in broad tissues. It is envisioned that the tail domains of other myosins are also likely responsible for much of their specific physiological functions.