Jump-starting kinesin

Abstract

When it is not actively transporting cargo, conventional Kinesin-1 is present in the cytoplasm in a folded conformation that cannot interact effectively with microtubules (MTs). Two important and largely unexplored aspects of kinesin regulation are how it is converted to an active species when bound to cargo and the related issue of how kinesin discriminates among its many potential cargo molecules. Blasius et al. (see p. 11 of this issue) report that either binding of the cargo linker c-Jun N-terminal kinase-interacting protein 1 (JIP1) to the light chains (LCs) or binding of fasciculation and elongation protein zeta1 (FEZ1) to the heavy chains (HCs) is insufficient for activation but that activation occurs when both are present simultaneously. A related paper by Cai et al. (see p. 51 of this issue) provides structural insight into the conformation of the folded state in the cell obtained by fluorescence resonance energy transfer analysis.

Figure 1.

Coiled-coil prediction for the HC of Drosophila Kinesin-1 and corresponding schematic representation of the domain organization. The two motor domains are connected to the neck coil by the neck linker and are followed by the long coiled-coil stalk composed of coil-1 and coil-2 (de Cuevas et al., 1992). The coiled-coil region near the N terminus of the LCs binds to coil-3 of the HCs (Diefenbach et al., 1998) to anchor the cargo-binding TPR domains of the LCs to the HCs. Coil-4a,b is a site for the binding of at least some cargoes to the HC, as first indicated by its importance for cargo transport in Neurospora crassa (Seiler et al., 2000) and later by the direct mapping of cargo-binding sites for animal kinesins. The whole region between aa 850–930 (aa 828–908 in rat and human kinesin) is highly conserved in animal kinesins and is predicted to be in a coiled-coil conformation when calculated with a window size of 28 residues, but with the aa 910–930 region (Coil-4c) more weakly predicted and in a different heptad frame. At the more stringent window size of 21 residues shown here, Coil-4c is not well predicted. Coil-4c is followed by a region with an excess of positive charge that is critical for both MT and head/neck interaction and by the highly conserved IAK (Stock et al., 1999) region that is required for the inhibition of ATPase in the folded conformation. The C-terminal region beyond the IAK domain is not well conserved and is likely to be unstructured.