# Molecular Mechanism of the Cytoplasmic Dynein-Dynactin Motor Complex

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $379,680

## Abstract

PROJECT SUMMARY/ABSTRACT
Title: Molecular Mechanism of the Cytoplasmic Dynein-Dynactin Motor Complex
Our long-term goal is to elucidate the molecular mechanism of the cytoplasmic dynein-dynactin motor complex,
and to define the molecular bases of dynein-related diseases in humans. The microtubule motor cytoplasmic
dynein, in cooperation with its regulatory proteins, drives several processes essential to embryonic
development, including neuronal proliferation, neuronal migration, and the transport of numerous intracellular
cargoes. Thus, it is not surprising dysfunction of dynein contributes to birth defects. A striking example is
lissencephaly (LIS), a rare, but devastating brain malformation. Variants of this diseases are caused by loss or
mutation of the dynein regulator Lis1. In lissencephaly, neurons fail to migrate properly during development
and affected infants’ brains lack the normal gyral folding pattern and layering of the cerebral cortex. These
children suffer untreatable epilepsy and severe psychomotor retardation, often dying in the first year of life.
Unfortunately, mechanistic insights into dynein function and its regulation by Lis1 are limited, hampering our
ability to understand the molecular basis for LIS, and other dynein-linked human diseases. In this proposal, we
will combine single-molecule fluorescence and optical tweezers-based force measurements with innovative
protein engineering to determine how cytoplasmic dynein in complex with its activator dynactin and the cargo
adaptor bicaudal D (BicD), is regulated by Lis1. We will decipher how Lis1 regulates the motion and force
generation of the dynein-dynactin-BicD (DDB) motor complex, and determine the effects of human disease
mutations on Lis1-DDB function. These studies will provide a new understanding of dynein-linked diseases,
and elucidate molecular targets for future therapeutic interventions.

## Key facts

- **NIH application ID:** 10366295
- **Project number:** 2R01GM098469-12
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Arne Gennerich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $379,680
- **Award type:** 2
- **Project period:** 2012-08-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366295

## Citation

> US National Institutes of Health, RePORTER application 10366295, Molecular Mechanism of the Cytoplasmic Dynein-Dynactin Motor Complex (2R01GM098469-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10366295. Licensed CC0.

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