The Role of Dynein in Disease

Abstract

Dynein is a minus end-directed microtubule motor involved in a very wide range of physiological activities, from ciliary and flagellar motility to a broad range of cytoplasmic functions. Most of the dozen or more forms of dynein found in vertebrates are axonemal, a term which refers to their association with the bundle of 20 microtubules plus accessory proteins that comprises the working core of both cilia and flagella. Cytoplasmic dyneins, in contrast, participate in diverse activities. The major form of cytoplasmic dynein, also referred to as MAP 1C or dynein 1, is present in all cell types, and is involved in mitosis, vesicular and nuclear transport, organizing and orienting the cytoplasmic microtubule network, and other functions. A second, minor form of cytoplasmic dynein, also referred to as DHC2b or dynein 2, has been implicated both in Golgi organization (Vaisberg et al., 1996) and in a recently discovered form of motility within cilia and flagella required for their growth and maintenance (Rosenbaum et al., 1999). This form of motility, referred to as intraflagellar transport (IFT), affects motile cilia and flagella, but also immotile primary cilia and the modified connecting cilia found in photoreceptor cells and other sensory neurons. All forms of dynein contain at least one, usually two, and in some organisms three motor domains (Fig. 20.1). Each motor domain represents the C-terminal two-thirds ( 350380 kDa) of a heavy chain (HC) subunit (Fig. 20.4). The Nterminal third of each HC also forms part of the base of the molecule. The motor domain region of the HC is highly conserved among dynein forms and throughout evolution. The N-terminal portion of the axonemal and cytoplasmic dynein HCs is considerably more divergent. The dyneins all have accessory subunits, which associate primarily with the Nterminus of the heavy chain and participate in cargo binding (Figs. 20.1 and 20.4). Intermediate chains (ICs), typically in the 70-kDa size range, are found in both cytoplasmic and axonemal dyneins. Several classes of light chain (LC) are also common to the two forms of dynein, whereas light intermediate chains