Paper

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

Rao, Lu, Benoit, Matthieu Pmh, Asenjo, Ana B, Sosa, Hernando J, Gennerich, Arne

2023

Overview

Mutations in the Kinesin-3 motor KIF1A, a microtubule (MT)-associated motor protein, cause devastating neurodevelopmental and neurodegenerative diseases termed KIF1A-associated neurological disorders (KAND). While the mechanism of KIF1A is increasingly understood, high resolution (<4 Å) structural information of KIF1A-MT complexes is lacking. Here, we present 2.7-3.4 Å resolution structures of dimeric MT-bound wild-type (WT) KIF1A and the pathogenic P305L mutant as a function of the nucleotide state. Our structures reveal that 1) the KIF1A dimer binds MTs in one- and two-heads-bound states, 2) that both MT-bound heads assume distinct conformations with tight inter-head connection, 3) the position and conformation of the class-specific loop 12 (the K-loop), and 4) that the P305L mutation causes structural changes in the K-loop that result in a weakly MT-bound state. Motivated by our structural insights, we performed structure-function studies that reveal that both the K-loop and head-head coordination are major determinants of KIF1A's superprocessive motility. Our work provides key insights into the mechanism of KIF1A and provides near-atomic structures of WT and mutant KIF1A for future structure-guided drug-design approaches to treat KAND.Competing Interest StatementThe authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press
• Subject: Drug development / Kinesin / Mutants / Mutation / Neurodegenerative diseases / Neurodevelopmental disorders / Neurological diseases / Structure-function relationships