14 April 2018 © Biochemical Society Movement and Motors Traffic control inside the cell: microtubule-based regulation of cargo transport Linda Balabanian, Abdullah R. Chaudhary and Adam G. Hendricks (McGill University, Canada) The cell relies on an intricate system of molecular highways and motors to transport proteins, organelles and other vesicular cargoes to their proper locations. Microtubules, long flaments that form a network throughout the cell, act as highways. The motor proteins kinesin and dynein associate with cargoes and transport them along microtubules. Rather than simply acting as passive tracks, microtubules contain signals that regulate kinesin and dynein to target cargoes to specifc locations in the cell. These signals include the organization of the microtubule network, chemical modifcations that alter the microtubule sur face properties and mechanics, and microtubule- associated proteins that modulate the motility of motor proteins and microtubule polymerization. How do PTMs control microtubule track stability and direct cargo trafcking? Microtubules are subject to multiple PTMs including acetylation, tyrosination and polyglutamylation (Figure 1). PTMs confer functional diversity to microtubules by altering their polymerization dynamics and mechanical properties. Microtubules are cylindrical polymers assembled from tubulin dimers. Most microtubule PTMs occur on the carboxy-terminal tail of tubulin that protrudes away from the microtubule surface, with the exception of acetylation that occurs in the lumen (the space inside the hollow cylinder). Importantly, PTMs also afect the electrostatic interactions between positively charged residues on motor proteins and MAPs and the negatively charged carboxy-terminal tails of tubulin. For instance, a positively charged lysine residue present in the TUBB3 isoform of tubulin decreases kinesin-1 processivity, while polyglutamylation, the addition of negatively charged glutamate residues on tubulin tails, increases processivity. Tubulin PTMs are correlated with the recruitment of specific types of motor proteins (Table 1). Lysosomes transported by kinesin-1 move along stable acetylated microtubules into neuronal axons, while lysosomes transported by kinesin-3 move along peripheral microtubules enriched with tyrosinated α-tubulin. Subcellular compartments such as dendrites and axons in neurons possess microtubules marked by different sets of PTMs (Figure 2). Kinesin-1 localization correlates with stable acetylated and detyrosinated microtubules in fibroblasts and neurons, while kinesin-3’s enrichment on tyrosinated microtubules directs cargoes towards the distal (i.e. A network of flaments called microtubules serve as tracks for organelles, vesicles, mRNA and signalling molecules inside the cell. Microtubules consist of a series of α-tubulin and β-tubulin heterodimers, assembled into long protoflaments, with approximately 13 protoflaments aligned in parallel to form a hollow microtubule cylinder. Microtubules constantly grow and shrink through the addition and loss of tubulin dimers. Microtubules are polar where growth is faster at the plus-end than the minus-end. In most cell types, microtubules are organized such that their minus-ends are located near the cell centre at the microtubule- organizing centre (MTOC), while their plus-ends extend toward the cell periphery (Figure 1). Kinesin and cytoplasmic dynein drive transport by using the energy from ATP hydrolysis to take successive steps along microtubules. Kinesins move towards the microtubule plus-end while dynein moves towards the minus-end. Both kinesins and dynein are bound to most cargoes, and these opposing teams of motors interact to drive transport in both directions. Robust control of intracellular transport is required to maintain proper signalling and degradative pathways, and defects result in developmental and neurodegenerative disease. The activity of kinesin and dynein is tightly regulated to target cargoes to specific locations in the cell in space and time. While the mechanisms that regulate intracellular transport are not well understood, recent studies suggest that cues embedded in the microtubule tracks act to direct transport. Several interdependent mechanisms affect motor protein motility including microtubule post- translational modifications (PTMs), microtubule- associated proteins (MAPs) and the organization of the microtubule network (Figure 1). Downloaded from http://portlandpress.com/biochemist/article-pdf/40/2/14/851779/bio040020014.pdf by guest on 21 September 2022