An Isoform of Microtubule-associated Protein 4 Inhibits Kinesin-driven Microtubule Gliding

Abstract

Recently, we revealed that microtubule-associated protein (MAP) 4 isoforms, which differ in the number of repeat sequences, alter the microtubule surface properties, and we proposed a hypothesis stating that the change in the surface properties may regulate the movements of microtubule motors [Tokuraku et al. (2003) J Biol Chem 278: 29609-29618]. In this study, we examined whether MAP4 isoforms affect the kinesin motor activity. When the MAP4 isoforms were present in an in vitro gliding assay, the five-repeat isoform but not the three- and four-repeat isoforms inhibited the movement of the microtubules in a concentration-dependent manner. The observation of individual microtubules revealed that in the presence of the five-repeat isoform, the microtubules completely stopped their movements or recurrently paused and resumed their movements, with no deceleration in the moving phase. The result can be explained by assuming that kinesin stops its movement when it encounters a microtubular region whose properties are altered by the MAPs. A sedimentation assay demonstrated that the MAP4 isoforms did not compete with kinesin for binding to microtubules, indicating that kinesin can bind to the MAP-bound microtubules, although it cannot move on them.

Stochastic models of intracellular transport

“…The second signaling mechanism involved microtubule associated proteins (MAPs). These molecules bind to microtubules and effectively modify the free energy landscape of motor-microtubule interactions (Telley et al, 2009;Tokuraku et al, 2007). For example, tau is a MAP found in the axon of neurons and is known to be a key player in Alzheimer's disease (Kosik et al, 1986).…”

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

“…Some of them, like tau or MAP2, induce MT bundling, whereas others like MAP4 do not have bundling activity (Burgin et al 1994;Kanai et al 1989Nguyen et al 1997;Olson et al 1995). In addition, MAP1B has been shown to control MT dynamic, while MAP4 alters MT surface properties and affects motor protein activity Samora et al 2011;Semenova et al 2014;Tokuraku et al 2007;Tortosa et al 2013;Utreras et al 2008). Interestingly, many of these MAPs not only bind MTs but also interact with actin and participate in numerous signal pathways.…”

“…The binding of MAP4 to MTs induces conformational changes that promote the overall MT stability (Xiao et al 2012). MAP4 has also been reported to alter the MT surface properties and affect kinesin-driven movement in vitro (Tokuraku et al 2007). In nonneuronal cells, overexpression of MAP4 inhibits organelle motility and trafficking, and it inhibits kinesin-driven MT gliding Tokuraku et al 2007).…”

“…MAP4 has also been reported to alter the MT surface properties and affect kinesin-driven movement in vitro (Tokuraku et al 2007). In nonneuronal cells, overexpression of MAP4 inhibits organelle motility and trafficking, and it inhibits kinesin-driven MT gliding Tokuraku et al 2007). In addition, it has been described to interact with p150Glued, part of the dynein-dynactin complex, and to inhibit dyneinmediated MT sliding (Samora et al 2011).…”

Kinesin-1 Traffic Control in Neuronal Highway

“…Among a large variety of identified MAPs, MAP2 as well as tau can inhibit the binding of kinesin-1 to microtubules and thereby lead to disrupted axonal transport (9). MAP4 is another MAP isoform that in contrast to MAP2 does not compete with kinesin-1 to bind to microtubules, but acts as roadblocks and can stop kinesin-1 motility by altering microtubular properties (10). Also, tau as a MAP is involved in the stabilization of microtubules.…”