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Kinesin-2 motors are known for their role in carrying cargo along microtubules and building cellular structures called cilia, but until now, the molecular mechanism that governs when and how they become active has remained unclear. The new study reveals how a small structural feature – the β-hairpin motif – in the tail of kinesin-2 plays a central role in keeping the motor in an inactive conformation. Using a combination of structural biology, single-molecule imaging, and live-cell assays, the collaborative work shows how this motif binds the motor domains and prevents them from engaging their microtubule track.

Activation occurs when kinesin-2 binds to a cargo adaptor such as APC, which interacts with the β-hairpin motif and occludes it – releasing the motor domains for movement along their track. This tightly regulated mechanism ensures that kinesin-2 activity is precisely coordinated with cargo binding and spatial requirements inside the cell.

“This discovery gives us a detailed structural framework for how kinesin-2 motors are turned on only when needed” said Dr Katerina Toropova. “It provides insight into how transport is controlled in processes ranging from cilia formation to neuronal cargo delivery” said Dr Anthony Roberts.

The study also highlights the importance of this regulatory system in vivo. Mutations that prevent autoinhibition lead to motor accumulation at the ciliary tip, impairing recycling and disrupting normal function – a finding with implications for understanding human ciliopathies.

With the β-hairpin motif conserved across eukaryotes, the work sheds light on an ancient and widespread mechanism for regulating motor proteins at the molecular level.

Artwork and molecular animation by Matthew Clark.