Biology subjects

Sosa, H. J.

Publications and source records attributed to Sosa, H. J..

2 recordsLinked to original sources

bioRxiv2023

High-Resolution structures of microtubule-bound KIF1A and its pathogenic variant P305L

Mutations in the microtubule-associated motor protein KIF1A lead to severe neurological conditions known as KIF1A-associated neurological disorders (KAND). Despite insights into its molecular mechanism, high-resolution structures of KIF1A-microtubule complexes remain undefined. Here, we present 2.7-3.4 [A] resolution structures of dimeric microtubule-bound KIF1A, including the pathogenic P305L mutant, across various nucleotide states. Our structures reveal that KIF1A binds microtubules in one- and two-heads-bound configurations, with both heads exhibiting distinct conformations with tight inter-head connection. Notably, KIF1As class-specific loop 12 (K-loop) forms electrostatic interactions with the C-terminal tails of both - and {beta}-tubulin. The P305L mutation does not disrupt these interactions but alters loop-12s conformation, impairing strong microtubule-binding. Structure-function analysis reveals the K-loop and head-head coordination as major determinants of KIF1As superprocessive motility. Our findings advance the understanding of KIF1As molecular mechanism and provide a basis for developing structure-guided therapeutics against KAND.

biochemistry↗

bioRxiv2019

Kinesin-5 promotes microtubule nucleation and assembly by stabilizing a lattice-competent conformation of tubulin

Besides sliding apart antiparallel microtubules during spindle elongation, the mitotic kinesin-5, Eg5 promotes microtubule polymerization, emphasizing its importance in mitotic spindle length control. Here, we characterize the Eg5 microtubule polymerase mechanism by assessing motor-induced changes in the longitudinal and lateral tubulin-tubulin bonds that form the microtubule lattice. Isolated Eg5 motor domains promote microtubule nucleation, growth and stability. Eg5 binds preferentially to microtubules over free tubulin, and colchicine-like inhibitors that stabilize the bent conformation of tubulin allosterically inhibit Eg5 binding, consistent with a model in which Eg5 induces a curved-to-straight transition in tubulin. Domain swap experiments establish that the family-specific Loop11, which resides near the nucleotide-sensing Switch-II domain, is necessary and sufficient for the polymerase activity of Eg5. Thus, we propose a microtubule polymerase mechanism in which Eg5 at the plus-end promotes a curved-to-straight transition in tubulin that enhances lateral bond formation and thereby promotes microtubule growth and stability.

biophysics↗