Microtubule severing enzymes oligomerization and allostery: a tale of two domains

Severing proteins are nanomachines from the AAA+ (ATPases associated with various cellular activities) superfamily whose function is to remodel the largest cellular filaments, microtubules. The standard AAA+ machines adopt hexameric ring structures for functional reasons, while being primarily monomeric in the absence of the nucleotide. Both major severing proteins, katanin and spastin, are believed to follow this trend. However, studies proposed that they populate lower-order oligomers in the presence of co-factors, which are functionally relevant. Our simulations show that the preferred oligomeric assembly is dependent on the binding partners, and on the type of severing protein. Essential dynamics analysis predicts that the stability of an oligomer is dependent on the strength of the interface between the helical bundle domain (HBD) of a monomer and the convex face of the nucleotide binding domain (NBD) of a neighboring monomer. Hot spots analysis found that the region consisting of the HBD tip and the C-terminal (CT) helix is the only common element between the allosteric networks responding to nucleotide, substrate, and inter-monomer binding. Clustering analysis indicates the existence of multiple pathways for the transition between the secondary structure of the HBD tip in monomers and the structure(s) it adopts in oligomers.