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bioRxiv · 10.64898/2026.03.27.714776

Kinase-gated coincidence detection controls kinesin-driven lysosome transport

O'Regan, L.·Bristow, S. A.·Anton, Z.·Bodzeta, A.·Cross, J. A.·Woolfson, D.·Dodding, M. P.
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Abstract

Kinesin motors drive long-range intracellular transport through coordinated cargo recognition and conformational autoregulation, yet the mechanisms that selectively control cargo engagement remain unclear. Here, we identify a phosphorylation-dependent gate on kinesin-1 activity mediated by the carboxy-terminal domain (CTD) of kinesin light chain 2 (KLC2). The KLC2 CTD is constitutively phosphorylated on multiple serine residues, suppressing membrane association via its amphipathic helix. We identify the NIMA-related kinase NEK10 as a KLC2-selective regulator of kinesin-1, restraining motor activation, cargo engagement, and lysosome transport; conversely, loss of NEK10 increases membrane association and, together with low-affinity adaptor interactions, promotes lysosome motility. These findings reveal a phosphorylation-regulated protein-lipid coincidence-detection mechanism - a kinesin-kinase code - that integrates adaptor binding with membrane cues to control kinesin-1-mediated transport and provide a mechanistic basis for understanding paralogue and isoform diversity in the kinesin-1 family.

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O'Regan, L., Bristow, S. A., Anton, Z., Bodzeta, A., Cross, J. A., Woolfson, D., Dodding, M. P.. 2026-03-28. Kinase-gated coincidence detection controls kinesin-driven lysosome transport. https://doi.org/10.64898/2026.03.27.714776

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