# Molecular Mechanism of the Cytoplasmic Dynein-Dynactin Motor Complex

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $359,050

## Abstract

PROJECT SUMMARY/ABSTRACT
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. Dynein
is the primary vehicle for microtubule minus-end-directed transport in eukaryotic cells. The
function and dysfunction of this vital motor and its regulatory proteins contribute to a broad range
of cellular functions and human diseases. Despite increasing efforts to define dynein’s functional
properties, the molecular mechanisms that govern dynein’s mechanochemistry remain poorly
understood. This deficiency largely stems from dynein’s structural complexity. Dynein belongs to
the AAA+ class of ATP-hydrolyzing mechanoenzymes that assemble into ring-shaped structures,
and therefore, possesses distinct structural features compared to the other two cytoskeletal motor
protein families, kinesin and myosin. Dynein is also exceptionally large (~1.4 MDa) and structure function
studies on dynein have been limited until recently by the availability of functional
recombinant dynein. Adding to dynein’s complexity, dynein associates with multiple accessory
chains and the dynactin complex, all of which are essential for nearly every cellular function of
dynein. Mutations in the dynein heavy chain and dynactin's largest subunit, p150glued, which
contains dynactin’s putative microtubule-binding domain, cause devastating neurological
diseases. However, mechanistic knowledge of dynein’s function—and therefore its dysfunction—
is limited compared to kinesin and myosin, which poses a major barrier for the development of
targeted therapies. In this grant, we seek to overcome these limitations by combining
ultrasensitive single-molecule assays with mutagenesis and structure-function studies. We will
employ S. cerevisiae, insect and human cell-based expression systems to produce stable
wildtype and mutant versions of both multiprotein complexes. Using these biochemical tools and
multicolor single-molecule fluorescence and optical tweezers methods, we will decipher the
molecular mechanism underlying the processive motion of the dynein-dynactin complex and
determine how dynactin regulates dynein force generation. This information will provide insights
into cellular physiology and identify targets within the dynein-dynactin complex for therapeutic
interventions.

## Key facts

- **NIH application ID:** 10126858
- **Project number:** 5R01GM098469-11
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Arne Gennerich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $359,050
- **Award type:** 5
- **Project period:** 2012-08-01 → 2022-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126858

## Citation

> US National Institutes of Health, RePORTER application 10126858, Molecular Mechanism of the Cytoplasmic Dynein-Dynactin Motor Complex (5R01GM098469-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10126858. Licensed CC0.

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