A Major Disease-Related Point Mutation in Spastin Dramatically Alters the Dynamics and Allostery of the Motor

• DOI: 10.1021/acs.biochem.4c00693
• Publication Date: 2025-02-26T17:51:12Z
• Authors: Shehani Kahawatte; Amanda C. Macke; Carter St. Clair; Ruxandra I. Dima
• Keywords: Dynamics

Spastin is a microtubule-severing AAA+ ATPase that highly expressed in neuronal cells and plays crucial role axonal growth, branching, regeneration. This machine oligomerizes into hexamers the presence of ATP microtubule carboxy-terminal tails (CTTs). Conformational changes spastin hexamers, powered by hydrolysis, apply forces to microtubule, ultimately leading severing filament. Mutations disrupt normal function spastin, impairing its ability sever microtubules effectively abnormal dynamics neurons characteristic set neurodegenerative disorders called hereditary spastic paraplegias (HSP). Experimental studies have identified HSP-related R591S (Drosophila melanogaster numbering) mutation as playing spastin. Given significant HSP, we employed combination molecular simulations with learning graph network-based approaches identify quantify perturbations caused HSP on spastin's allostery functional implications. We found hexamer, upon mutation, loses execute primary motion associated action. The study allosteric showed regions are most perturbed those involved formation interprotomer contacts. induces rigidity networks motor, making it more likely experience loss applied would not be easily dissipated passing through variety alternative paths wild-type (WT)