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Intrinsic disorder in the kinesin superfamily

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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, 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 the ID may be a critical structural element for determining the functional specificity of individual kinesins. To support this concept, we present a systematic analysis of the kinesin superfamily, family by family, for predicted ID regions. 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 the ID residue is a structural element utilized by the kinesin superfamily in order to impart functional specificity to individual kinesins.

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Abbreviations

ID:

Intrinsic disorder/intrinsically disordered

MT:

Microtubule

PTM:

Post-translational modification

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Acknowledgments

We wish to acknowledge members of the Rice lab for their contributions and the NIH for support (Molecular Biophysics Training Program grant 5 T32 GM008382 to M.A.S. and R01GM072656 to S.E.R.).

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  1. Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, IL, 60611-3008, USA

    Mark A. Seeger & Sarah E. Rice

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  1. Mark A. Seeger
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  2. Sarah E. Rice
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Correspondence to Sarah E. Rice.

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Figure S1:

Sites of ligand binding and PTM correlate with regions of ID. The ID prediction plots and sites of experimentally determined ligand binding and PTM are aligned with the predicted topology diagrams for each kinesin in the human complement, family by family. 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 if 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 (138 total) and PTM (42 total) 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 asterisk (100/138 = 72.5 %), and PTM residues or sites that contain predicted ID residues are indicated with hash marks (38/42 = 90.5 %). (PDF 4600 kb)

Figure S2

ID in the kinesin motor domain. The kinesin motor domains contain disordered loops. A The crystal structure of the Kif5B monomeric motor (PDB: 1MKJ) is shown as a ribbon diagram, with the ADP molecule shown as a space-filling model. The surface-accessible loops are highlighted in red and labeled as indicated. The P-loop, Switch I, Switch II, and the neck-linker are highlighted in blue and labeled as indicated. B The frequencies with which each indicated structural element of the kinesin motor domain in a given kinesin subfamily was predicted to be disordered are listed in this table. The N-terminus, L1, L4/P-loop, L7, Switch I, L10, Switch II, L12, and the neck-linker are the motor elements most often predicted to be disordered. N N-terminus, L loop. (PDF 4600 kb)

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Seeger, M.A., Rice, S.E. Intrinsic disorder in the kinesin superfamily. Biophys Rev 5, 233–247 (2013). https://doi.org/10.1007/s12551-012-0096-5

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