Cargo transport: molecular motors navigate a complex cytoskeleton
Introduction
Cargo transport of organelles, secretory vesicles, and protein complexes by tiny molecular motors is an essential intracellular process. The importance of this process is emphasized by mutations to these motors lead to genetic diseases such as amyotrophic lateral sclerosis [1], parapalegia [2], and Griscelli syndrome type 1 [3]. Molecular motors that drive cargo transport along the cytoskeletal highway include myosins traveling along actin filaments and kinesin and cytoplasmic dynein motors traveling on microtubules (Figure 1). These motors share cargo transport duties and face the challenge of maneuvering through a complex cytoskeleton with numerous microtubule and actin filament intersections. How these motors navigate these obstacles and whether they work together to assure that cargo reaches its final destination is still unclear. In this review, we will highlight recent single molecule in vitro experiments that characterize the transport capacity of individual and small ensembles of molecular motors along constructed cytoskeletal networks. We will discuss how these results contribute to our understanding of intracellular cargo transport in vivo.
Section snippets
Cargo transport and track switching
Both the secretory and endocytic pathways require that vesicular cargo be transferred between actin and microtubule tracks. Ideally, microtubules originate from an organizing center near the nucleus and fan out with their plus ends toward the cell periphery. Cargos (e.g. secretory vesicles) carried by plus end directed kinesins are translocated along microtubules toward the cortex. Upon reaching the dense cortical actin meshwork the cargo is transferred to myosin Va for delivery to the cell
Inherent motor properties crucial for cargo transport
All three motor types described here (i.e. myosins, kinesins, and cytoplasmic dyneins) have two motor domains that hydrolyze ATP and convert chemical energy into force and motion. These two motor domains are highly coordinated so that the molecule steps processively in a hand-over-hand fashion, taking multiple steps before diffusing away from its track [11•, 12, 13, 14]. Although, a single processive motor can, in principle, act as a cargo transporter, it is more likely that several motors are
In vitro maneuvering through intersections
A recent series of experiments take a bottom-up approach to build complexity by constructing a simple model of the cytoskeleton on a glass coverslip. By adhering isolated actin filaments and/or microtubules to form filament intersections, one can observe how a single motor, or a small ensemble of motors attached to a bead, navigates an intersection (Figure 2).
Conclusions
With the advent of single molecule biophysical techniques, the recent flurry of in vivo and in vitro studies have provided significant insight to how molecular motors manage to transport and deliver cargo within the cell. However, many questions still remain that pose experimental challenges. For example, in vitro studies must build further complexity to characterize how cargo with mixed populations of actin and microtubule-based motors navigate through a well-defined three-dimensional array of
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
JLR would like to thank the Goldman and Holzbaur laboratories and DMW and MYA the Trybus and Warshaw laboratories for numerous discussions that helped formulate our thoughts around issues presented in this review. DMW and MYA were supported by funds from the National Institutes of Health (HL059408, HL085489).
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