Bicaudal-D: Switching motors, cargo and direction

Scope of this thesis Transport of vesicles and organelles is an essential cellular process. Proteins like Rab GTPases, specialized adaptor proteins and motor proteins are involved in targeting and movement of cargos to their destination. This thesis describes the function of the mammalian adaptor protein Bicaudal-D in intracellular transport and its potential role in bidirectional movement of several cargos. Chapter 1 gives an overall introduction of the components involved in transport mechanisms. It starts with a description of the three major types of cytoskeletal filaments, actin, intermediate filaments and microtubules. Subsequently, microtubule associated proteins and motor proteins are discussed in more detail. Chapter 1 concludes with a description of Bicaudal-D, its role in Drosophila development and the function of Bicaudal-D in cargo transport along the microtubules in mammalian cells. Chapter 2 describes the behaviour of vesicles associated with the small GTPase Rab6. It shows that Rab6 is a marker of exocytotic vesicles that are mainly driven by the microtubule plus-end directed motor kinesin-1. Chapter 3 reports a novel interaction partner of mammalian Bicaudal-D, RanBP2. Bicaudal-D binds RanBP2 in the late G2/early prophase and through this interaction targets the microtubule minus end-directed dynein/dynactin motor complex to the nuclear envelope. This interaction contributes to the positioning of the nucleus in close proximity of the microtubule organising centre prior to mitosis. Chapter 4 shows that the N-terminal part of Bicaudal-D acts as a linker between cytoplasmic dynein and its accessory complex dynactin. It explores this finding in the context of dynein motility in vitro. Chapter 5 reviews the role of Rab GTPases in the movement of membrane organelles and discusses several well-studied examples of intracellular transport, such as aggregation and dispersion of melanosomes in pigment cells. The described transport systems are compared with the model of Bicaudal-D function that emerged from the experimental work described in this thesis.