Mechanism of microtubule severing enzymes

National Institute Of Neurological Disorders And Stroke

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Abstract

Cells constantly assemble and disassemble their microtubule cytoskeleton through the concerted action of microtubule polymerases, depolymerases, crosslinkers and severing enzymes. Microtubule severing enzymes spastin and katanin generate internal breaks in microtubules. They are are critical in a wide range of cell biological processes including biogenesis of neuronal and non-centrosomal microtubule arrays, phototropism, spindle scaling, chromosome segregation, and control of centriole and cilia numbers. Mutations in microtubule severing enzymes cause severe neurodegenerative and neurodevelopmental disorders. Mutations in spastin are responsible for more than 40% of hereditary spastic paraplegia cases. Mutations in katanin cause microcephaly. The mechanism used by these enzymes to destabilize the microtubule and their effect on microtubule dynamics and the morphology of microtubule networks is still poorly understood. This year we have continued our studies into the structure of microtubule severing enzymes in complex with their regulators using cryo-EM and single molecule fluorescence imaging and we have identified mechanisms of their regulation by accessory factors such as neuronal structural MAPs. We have also been working with clinicians to characterize several newly identified spastin and katanin mutations in patients using structural modeling.