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Pathogenic KIF1A R350 Variants Disrupt A Conserved Kinesin-Tubulin Salt Bridge.

Abhipsa Shatarupa1, Lu Rao1, Ana Asenjo1

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Pathogenic KIF1A mutations disrupt a key salt bridge, altering motor function in KIF1A-associated neurological disorder (KAND). This structural insight explains how these mutations impact kinesin motility and disease.

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Area of Science:

  • Molecular Biology
  • Neuroscience
  • Structural Biology

Background:

  • Kinesin motor protein KIF1A is crucial for neuronal function.
  • Pathogenic variants in KIF1A cause KIF1A-associated neurological disorder (KAND).
  • Mutations at KIF1A residue R350 are linked to hereditary spastic paraplegia and altered motor function, but the structural basis is unknown.

Purpose of the Study:

  • To elucidate the structural basis of KIF1A R350 mutations in KAND.
  • To investigate the interaction between KIF1A and microtubules at residue R350.

Main Methods:

  • High-resolution cryo-electron microscopy (cryo-EM) to determine structures of KIF1A R350G and R350W mutants bound to microtubules.
  • Single-molecule assays to assess motor function, including velocity and processivity.

Main Results:

  • Identified a novel salt bridge between KIF1A R350 and α-tubulin E415.
  • Observed disruption of this salt bridge in R350G and R350W mutants.
  • Demonstrated that disruption correlates with increased KIF1A velocity and reduced processivity.

Conclusions:

  • A conserved electrostatic interaction at the motor-microtubule interface regulates KIF1A motility.
  • Disruption of the R350 salt bridge contributes to KAND pathogenesis.
  • Structural understanding of KIF1A mutations provides insights into neurodegenerative disease mechanisms.