# Multimotor Mechanisms in Microtubule-based Transport

> **NIH NIH R01** · PENNSYLVANIA STATE UNIVERSITY, THE · 2020 · $318,780

## Abstract

PROJECT SUMMARY
 Intracellular cargo transport along microtubules is driven by kinesin and dynein motors that work
antagonistically to precisely target cargo to specific cellular locations. Although the mechanisms
underlying bidirectional transport have received considerable attention, a number of very fundamental
questions remain, and a better quantitative understanding of molecular interactions and
mechanochemistry underlying the regulation of bidirectional transport is essential for the field to move
forward. In this work we will use DNA origami to create complexes with defined numbers of kinesin and
dynein motors in vitro, and use Interfoerometric Scattering (iSCAT) microscopy to track them with 1 ms
and 2 nm resolution. In parallel, we will model the transport using Brownian dynamics simulations to
uncover the molecular-level details underlying the experimentally observed behavior. Our goal is to
understand how the contrasting single-motor properties kinesin-1, -2, and -3 family motors manifest
themselves in multi-motor teams, how roadblocks on microtubules alter bidirectional transport, and what
role membrane fluidity plays in altering multi-motor transport properties. Aim 1 focuses on analyzing the
movement of cargo transported by teams of similar and dissimilar kinesin motors to understand how
differences in motor attachment rates and load-dependent detachment alter multi-motor behavior. Aim 2
will extend this to studying cargo functionalized with kinesin and activated mammalian cytoplasmic
dynein complexes containing dynein, dynactin, and the activator BicD2. The switching behavior of
different kinesins against their natural opponent will be of particular interest and will require high-
resolution tracking in conjunction with experimentally constrained models. In Aim 3 we will attach motors
to supported lipid bilayers and vesicles, measure their transport dynamics, and computationally model
the underlying motor diffusion and bilayer deformation. We hypothesize that by acting as a “shock
absorber”, the fluid bilayer will reduce inter-motor forces, and that motor diffusion in the bilayer will lead
to clustering that enhances motor performance in manner similar to integrins in focal adhesions.
 Although bidirectional transport can be described as a “tug-of-war” between kinesin and dynein
pulling in opposite directions, this model fails to account for a large body of experimental observations.
This gulf between molecular-level understanding of motors in vitro and observed transport of cargo in
cells must be bridged to understand the role of tau tangles in Alzheimers' disease, the deterioration of
axonal transport in Huntington's and Parkinson's disease, and other neurodegenerative disorders that
involve defects in microtubule-based bidirectional transport.

## Key facts

- **NIH application ID:** 9853807
- **Project number:** 5R01GM121679-04
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** William Olaf Hancock
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $318,780
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853807

## Citation

> US National Institutes of Health, RePORTER application 9853807, Multimotor Mechanisms in Microtubule-based Transport (5R01GM121679-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9853807. Licensed CC0.

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