Hijacking Hinges: Cracking the coiled-coil code to control intracellular transport

Kinesin and dynein motors transport cargo bidirectionally along microtubules. Proper regulation is essential for cellular health, and its disruption is linked to neurodegeneration, cardiac disease, and cancer. Motor proteins and adaptors are autoinhibited and activated by specific motor-cargo–adaptor interactions. Coiled-coil domains are highly conserved in motors and adaptors and are emerging as dynamic regulatory elements.This project tests the hypothesis that “coiled-coil hinges” are fundamental regulatory elements in transport systems and can be manipulated to target motor dysfunction in disease. Our proof of concept work on kinesin 1 uncovered a novel autoinhibitory mechanism involving a coiled-coil hinge. I designed a conformational switch, triggered by a cell-penetrating peptide, to activate kinesin-1 allosterically. I will extend this approach to BicD2, the most intensively studied dynein adaptor. Mutations in BicD2 cause neuromuscular and developmental disorders and viruses and bacteria hijack BicD2 to subvert dynein; however, its regulatory mechanisms remain poorly defined. I will elucidate the mechanisms of coiled-coil regulation in BicD2, engineer switchable variants to control dynein activation, and explore how coiled-coil adaptors regulate bidirectional transport more broadly. This work will deepen mechanistic understanding of motor protein regulation and pave the way for novel therapeutic strategies for diseases associated with motor dysfunction.