Intracellular Cargo Transport by Kinesin-3 Motors

Abstract

Intracellular transport along microtubules enables cellular cargoes to efficiently reach the extremities of large, eukaryotic cells. While it would take more than 200 years for a small vesicle to diffuse from the cell body to the growing tip of a one-meter long axon, transport by a kinesin allows delivery in one week. It is clear from this example that the evolution of intracellular transport was tightly linked to the development of complex and macroscopic life forms. The human genome encodes 45 kinesins, 8 of those belonging to the family of kinesin-3 organelle transporters that are known to transport a variety of cargoes towards the plus end of microtubules. However, their mode of action, their tertiary structure, and regulation are controversial. In this review, we summarize the latest developments in our understanding of these fascinating molecular motors.

Fig. 1. Kinesin-3 tree.

Phylogenetic tree of all kinesin-3 family members from Homo sapiens (Hs), Drosophila melanogaster (Dm), Caenorhabditis elegans (Ce), Ustilago maydis (Um), Aspergillus nidulans (An), Neurospora crassa (Nc), and Dictyostelium discoideum (Dd). Selected kinesin-3 members from Rattus norvegicus (Rn), Gibberella moniliformis (Gm), and Cochliobolus heterostrophus (Ch) are also shown. Subfamilies are indicated in bold font. Human KIF5A, a kinesin-1, was used as root (shown in gray). To calculate tree information in Clustal Omega [130], kinesin motor domain sequences were aligned and cropped to a ~330-bp-long conserved region. The tree information was then used to generate a radial tree using T-REX tree viewer [131].

Fig. 2. Structure of kinesin-3 motors.

a) Primary structure of human kinesin-3 members with characteristic N-terminal motor domain, FHA domain, and tail with several short coiled-coil (CC) regions in addition to a variety of protein or lipid interaction motifs. b) Schematic representation of a dimeric kinesin-3 motor and its interaction with the microtubule surface as well as a cargo vesicle. c) Structural model of kinesin motor domains binding to the microtubule (one αβ - tubulin heterodimer shown, in gray). The flexible C-terminal tubulin tails (E-hooks) are indicated in green. Key regions of the kinesin motor domain (blue) that contribute to interaction with microtubules are highlighted in red for both KIF5A, a kinesin-1, and KIF1A, a kinesin-3. Key residues that were shown to contribute to 10-fold higher processivity of kinesin-3 are shown in magenta [53, 54]. PDB accession numbers: 4UXP and 4UXY.