Intrinsic Disorder in the Kinesin Superfamily - PubMed (original) (raw)

Intrinsic Disorder in the Kinesin Superfamily

Mark A Seeger et al. Biophys Rev. 2013.

Abstract

Kinesin molecular motors perform a myriad of intracellular transport functions. While their mechanochemical mechanisms are well understood and well-conserved throughout the superfamily, the cargo-binding and regulatory mechanisms governing the activity of kinesins are highly diverse and in general, are incompletely characterized. Here we present evidence from bioinformatic predictions indicating that most kinesin superfamily members contain significant regions of intrinsically disordered (ID) residues. ID regions can bind to multiple partners with high specificity, and are highly labile to post-translational modification and degradation signals. In kinesins, the predicted ID regions are primarily found in areas outside the motor domains, where primary sequences diverge by family, suggesting that ID may be a critical structural element for determining the functional specificity of individual kinesins. To support this idea, we present a systematic analysis of the kinesin superfamily, family by family, for predicted regions of ID. We combine this analysis with a comprehensive review of kinesin binding partners and post-translational modifications. We find two key trends across the entire kinesin superfamily. First, ID residues tend to be in the tail regions of kinesins, opposite the superfamily-conserved motor domains. Second, predicted ID regions correlate to regions that are known to bind to cargoes and/or undergo post-translational modifications. We therefore propose that ID is a structural element utilized by the kinesin superfamily in order to impart functional specificity to individual kinesins.

Keywords: Cargo; Intrinsic Disorder; Kinesin; Microtubule; Motor Protein; Regulation.

PubMed Disclaimer

Figures

Fig. 1

Fig. 1

Sites of ligand binding and post-translational modifications (PTMs) correlate with regions of intrinsic disorder (ID). The prediction plots for ID and sites of experimentally determined ligand binding and PTM are aligned with the predicted topology diagrams for a selection of six human kinesins. Regions of known structure, such as the motor or small globular domains, or regions of predicted coiled-coil are designated with colored bars, as indicated. Regions of unknown structure are indicated with a black line. The ID prediction plots from Seeger et al. (2012) are superimposed in blue onto kinesin topology diagrams, such that the midline of the topology diagram lines up with the cutoff value used to predict whether a residue is ordered or disordered. Therefore, residues for which the blue ID prediction plots are at or above the midline of the topology diagrams are predicted to be disordered, and residues for which the blue ID prediction plots are below the midline of the topology diagrams are predicted to be ordered. The experimentally determined ligand-binding and PTM sites, as described in the cited literature, are indicated by the black bars below the topology diagrams and with normal and italic text, respectively. Ligand-binding sites that contain a greater percentage of predicted ID residues than a random segment of the same number of residues from the same molecule are indicated with an asterisk (100/138 = 72.5 % for the entire human kinesin complement), and post-translationally modified residues or sites that contain predicted ID residues are indicated with hash marks (38/42 = 90.5 % for the entire human kinesin complement). Multiple hash marks indicate multiple modified residues. HhH helix–hairpin–helix, SAM sterile alpha motif

Fig. 2

Fig. 2

Purposes of ID in the kinesin superfamily. A generic kinesin molecule is drawn with the motor domains in blue, the coiled-coil stalks in green, and disordered loops or domains of the motor, stalk, and tail in purple. The proposed applications of ID in kinesin molecules are illustrated. These uses include facilitating the microtubules and ATP and neck-linker interactions necessary for motility, providing the structural flexibility and intramolecular interactions the enable the formation of auto-regulated conformations, facilitating cargo binding with or without coordinated folding of the ID binding-site, and accommodating PTMs

Similar articles

Cited by

References

    1. Abaza A, Soleilhac JM, Westendorf J, Piel M, Crevel I, Roux A, Pirollet F. M phase phosphoprotein 1 is a human plus-end-directed kinesin-related protein required for cytokinesis. J Biol Chem. 2003;278(30):27844–27852. doi: 10.1074/jbc.M304522200. - DOI - PMC - PubMed
    1. Asaba N, Hanada T, Takeuchi A, Chishti AH. Direct interaction with a kinesin-related motor mediates transport of mammalian discs large tumor suppressor homologue in epithelial cells. J Biol Chem. 2003;278(10):8395–8400. doi: 10.1074/jbc.M210362200. - DOI - PubMed
    1. Ashar HR, James L, Gray K, Carr D, Black S, Armstrong L, Bishop WR, Kirschmeier P. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J Biol Chem. 2000;275(39):30451–30457. doi: 10.1074/jbc.M003469200. - DOI - PubMed
    1. Bartels T, Choi JG, Selkoe DJ. alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature. 2011;477(7362):107–110. doi: 10.1038/nature10324. - DOI - PMC - PubMed
    1. Bieling P, Telley IA, Piehler J, Surrey T. Processive kinesins require loose mechanical coupling for efficient collective motility. EMBO Rep. 2008;9(11):1121–1127. doi: 10.1038/embor.2008.169. - DOI - PMC - PubMed

LinkOut - more resources