# Structure and Mechanism of the Kinesin-3 Motor KIF1A

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $621,671

## Abstract

Our goal is to define the structural and functional mechanism by which the kinesin-3 motor KIF1A
generates force and moves along microtubules, and to define the structural basis of KIF1A-related
human diseases. The microtubule (MT) transport system regulates essential eukaryotic activities,
including neuronal cell division, neuronal migration and the transport of subcellular cargoes.
KIF1A, a member of the kinesin-3 family of MT-associated motor proteins, is a key mediator of
these activities as the major generator of MT plus-end-directed motility in neurons. KIF1A’s
cargoes include nuclei in dividing brain stem cells and synaptic vesicle precursors and dense core
vesicles in axon terminals. Not surprisingly, its dysfunction is implicated in a growing number of
neurodevelopmental and neurodegenerative disorders referred to as KIF1A-associated
neurological disorder (KAND). Unfortunately, these diseases remain poorly understood, in part
because KIF1A’s molecular mechanism remains unclear. For example, while most mutations
occur in KIF1A’s motor domain, high-resolution structures of the KIF1A-MT complex do not exist.
In addition, it remains unknown why Kif1A is superprocessive but easily gives up under load. In
this proposal, we will combine cryo-electron microscopy, single-molecule fluorescence, and
optical tweezers-based force measurements with innovative protein engineering to determine why
KIF1A is a weak but superprocessive motor, define high-resolution structures of the KIF1A-MT
complex as a function of KIF1A’s mechanochemical cycle and determine the structural defects
caused by disease mutations in KIF1A. These studies will provide a new understanding of KAND
and elucidate molecular targets for therapeutic interventions.

## Key facts

- **NIH application ID:** 10909312
- **Project number:** 5R01GM147332-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Arne Gennerich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $621,671
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909312

## Citation

> US National Institutes of Health, RePORTER application 10909312, Structure and Mechanism of the Kinesin-3 Motor KIF1A (5R01GM147332-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10909312. Licensed CC0.

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