# Cryo-EM unveils kinesin KIF1A’s processivity mechanism and the impact of its pathogenic variant P305L

## TL;DR

Cryo-EM structures of KIF1A reveal how it binds microtubules and how a disease-causing mutation affects its function.

## Contribution

High-resolution structures of KIF1A and its P305L mutant provide new insights into its processivity mechanism and disease impact.

## Key findings

- KIF1A binds microtubules in one- and two-heads-bound configurations with tight inter-head connections.
- The P305L mutation alters loop-12 conformation, impairing strong microtubule binding despite preserving electrostatic interactions.
- The K-loop and head-head coordination are key to KIF1A’s superprocessive motility.

## Abstract

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 2.7-3.5 Å 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, KIF1A’s class-specific loop 12 (K-loop) forms electrostatic interactions with the C-terminal tails of both α- and β-tubulin. The P305L mutation does not disrupt these interactions but alters loop-12’s conformation, impairing strong microtubule-binding. Structure-function analysis reveals the K-loop and head-head coordination as major determinants of KIF1A’s superprocessive motility. Our findings advance the understanding of KIF1A’s molecular mechanism and provide a basis for developing structure-guided therapeutics against KAND.

Benoit et al. present high-resolution structures of dimeric microtubule-bound KIF1A, including its pathogenic P305L mutant. Their findings provide insights into KIF1A’s motility mechanism and potential therapies for associated neurological disorders.