Intrinsic disorder in the kinesin superfamily

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.

SKIP controls lysosome positioning using a composite kinesin-1 heavy and light chain-binding domain

“…Consistent with the studies of Hackney (Hackney, 2007) and Rice (Seeger and Rice, 2013), analysis of the KHC C-terminal region using Pcoils (Lupas et al, 1991) indicated that most of the KHC tail construct is comprised of a coiled coil or series of coils, which terminate between amino acids 900 and 910. Further analysis using Disopred3 (Jones and Cozzetto, 2015) suggests that the most C-terminal region is unstructured (Fig.…”

FUS inclusions disrupt RNA localization by sequestering kinesin-1 and inhibiting microtubule detyrosination

“…S3 C). Nevertheless, it is interesting that various kinesins, including kinesin-1, are predicted to contain significant regions of intrinsically disordered regions (IDRs; Seeger and Rice, 2013). IDR interactions have been proposed to mediate the recruitment of proteins into phase-separated granules (Kato et al, 2012;Lin et al, 2015), suggesting the possibility that IDR interactions might mediate sequestration of kinesin in cytoplasmic FUS granules.…”

Condensin I-mediated mitotic chromosome assembly requires association with chromokinesin KIF4A

“…2A; for review, see Seeger and Rice 2013). To determine which of the KIF4A domains mediates the interaction, we performed pull-down assays using purified recombinant protein fragments fused with GST.…”