The diffusive interaction of microtubule binding proteins
Introduction
The microtubule cytoskeleton provides the scaffold for a multitude of protein–protein interactions. Proteins that are able to bind directly to microtubules form a diverse ensemble referred to as microtubule binding proteins. Microtubule binding proteins, when examined at the level of single molecules, tend not to remain statically bound to the microtubule, but instead travel along the surface of the microtubule. Perhaps the most familiar example of such translocation is the directed motility exhibited by kinesin molecules, which step in a constant direction along the microtubule lattice. However a second mechanism, referred to as diffusional motility (Figure 1), has generated a significant amount of interest as an increasing number of microtubule binding proteins have been found to exhibit this behavior. Diffusional motility may even contribute to the stepping mechanism in kinesins by means of a diffusional search process of the free motor domain head [1] (also see companion review in this issue from Gennerich and Vale).
Diffusional motility is defined as a one-dimensional (1D) random walk along the microtubule lattice driven solely by thermal energy. The equations characterizing these motions are identical to those of classical Brownian motion, although the diffusion coefficients tend to be significantly lower [2, 3, 4••, 5•]. Interestingly, such a reduction in diffusional speed has been predicted by models of DNA binding proteins [6]. This model assumes that 1D diffusion is limited not only by the binding protein's three-dimensional translational diffusion coefficient, but also by its rotational diffusion coefficient. Similar to a key sliding into a lock, the protein must adopt the correct rotational orientation before advancing along the polymeric filament. Any rotation away from the correct orientation will stall its progress.
Section snippets
Survey of microtubule binding proteins that exhibit 1D lattice diffusion
Some of the earliest single molecule observations of diffusional motion on the microtubule lattice were made while studying the directed motility of kinesin molecules [7, 8]. Kinesin motor domains can bind strongly to the microtubule, which allows for the directed ‘hand-over-hand’ motility characteristic of kinesin superfamily members. However, this process requires that the kinesin molecule's trailing head disengage (calling for a weakly bound state) while the leading head remains strongly
Advantages of microtubule lattice diffusion as a transport mechanism
Clearly, the phenomenon of microtubule lattice diffusion is a ubiquitous mechanism occurring across a diverse set of microtubule binding proteins. Importantly, diffusional motility holds several key advantages over classical directed motility. First, as pure diffusion is by definition unbiased, it allows the binding protein to reach either end of the microtubule [18]. Significantly many of the microtubule binding proteins that exhibit pure diffusion have a function that requires localization to
DNA binding proteins — an analog for diffusion of microtubule binding proteins
The concept of microtubule binding proteins diffusing along the microtubule lattice has only recently evolved into a significant area of research. However, the similar phenomenon of DNA binding proteins diffusing along DNA strands has been intensely studied for decades [23, 24, 25, 26•]. Although the structures of DNA and microtubule biopolymers are radically different, the overall 1D morphology and strong negative surface charge that they have in common makes this a potentially enlightening
The diffusive binding interaction: flexible and nonspecific
A question remains as to the nature of the interaction that would allow such freedom of motion without complete detachment from the microtubule lattice. Commonly, the binding interaction is thought to be purely electrostatic in nature because of the observation that the microtubule surface carries a strong negative surface charge and binding proteins tend to hold a net positive charge. This is additionally supported by studies that have shown that proteolytic removal of the microtubule's
Conclusions
Microtubule lattice diffusion is a widespread and effective mode of protein transport along microtubules. The fact that such a diversity of microtubule binding proteins exhibit this behavior has hindered attempts to develop a unifying description of the mechanism. However, microtubule-based diffusional motility shares important similarities with the well-studied subject of DNA-based diffusion (including comparable diffusion coefficients and a common electrostatic component of the interaction).
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors acknowledge support from the National Institutes of Health and from the National Science Foundation (IGERT traineeship to JC and NIH grant GM69429 to LW). We thank Chip Asbury and Mike Wagenbach for their insightful comments and suggestions.
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