# Mechanisms of Lis1 and NudE/L Regulation of the Molecular Motor Dynein

> **NIH NIH R00** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $249,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Microtubule-based transport is required for cell division, cell migration, and for transport of a number of cellular
cargoes. A number of neurodevelopmental and neurodegenerative diseases are caused by or associated with
impaired microtubule-based transport. Cytoplasmic dynein 1 (dynein) is one of two molecular motor proteins
that are responsible for microtubule-based transport. Dynein is a highly regulated motor and interacts with a
number of adaptor proteins that modulate its function and activity. Mutations or copy number variations of
dynein regulatory proteins also leads to neurodevelopmental diseases. Despite the importance to human
health, mechanisms of how dynein is regulated are largely unknown. This proposal for an NIH K99/R00
Pathway to Independence Award seeks to understand how Lis1 and NudE/L, which are two regulators required
for nearly every dynein function, modulate dynein activity. Impaired Lis1 and NudE/L function is implicated in a
number of human diseases, including microcephaly, lissencephaly, schizophrenia, and autism. In Aim1 during
the mentored phase of the award, Dr. DeSantis will determine how Lis1 and NudE/L alter dynein function using
a combination of structural biology and pure protein reconstitution experiments. Phosphorylation of dynein,
Lis1, and NudE/L alter their activity but the mechanism of how this occurs in unknown. During the independent
phase of the award, Dr. DeSantis will also determine how post-translational modifications influence dynein,
Lis1, and NudE/L activity. In Aim 2, Dr. DeSantis will identify novel dynein regulatory pathways using a
combination of proteomics, cell biology, live cell imaging, and recombinant protein reconstitutions. Dr. DeSantis
has already identified novel Lis1 and NudE/L interacting proteins and will elucidate their function and
mechanism during the mentored and independent award phase. The results of this work will reveal
mechanisms of dynein regulation, which has far reaching implications in human health and disease. Dr.
DeSantis will receive training in cryo-electron microscopy in the K99 portion of the award. When combined with
her background in biochemistry, cell biology, and live cell imaging, learning cryo-electron microscopy will
empower Dr. DeSantis' research about mechanisms of motor protein regulation far beyond the duration of the
K99/R00 award.

## Key facts

- **NIH application ID:** 10087571
- **Project number:** 4R00GM127757-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Morgan DeSantis
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2018-09-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10087571

## Citation

> US National Institutes of Health, RePORTER application 10087571, Mechanisms of Lis1 and NudE/L Regulation of the Molecular Motor Dynein (4R00GM127757-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10087571. Licensed CC0.

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