A unified mechanism for tubulin cofactors catalyzing α/β-tubulin biogenesis and degradation
We solved a decades-old mystery in cell biology by revealing how a group of proteins called tubulin cofactors build and dismantle the molecular building blocks of the cell’s internal skeleton. Using cryo-electron microscopy, we captured this molecular machine frozen at each stage of its cycle, showing precisely how it malfunctions in children with rare neurological diseases such as infantile encephalopathy and corpus callosum hypoplasia. We found that the cofactor complex operates like a spring-loaded cage — securing β-tubulin, then using a lever-arm rotation driven by the Arl2 GTPase to snap α-tubulin into place, forming the αβ dimers that cells need to build healthy microtubules; when dimers are not needed, the machine reverses, pulling the pair apart and preventing the freed β-tubulin from forming toxic homodimers. Our findings open a concrete path toward gene therapies for these incurable diseases and may accelerate diagnosis for children currently lost in years-long genetic odysseys with no clear answer.