# Dynein-adaptor interaction mechanisms and malfunction at atomic resolution

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $325,082

## Abstract

Project Summary
Neurodegenerative diseases are mostly incurable conditions that result in progressive degeneration or
death of nerve cells. Prominent examples such as Spinal Muscular Atrophy (SMA) are caused by
mutations in the cytoplasmic dynein multi-protein complex. Dynein 1 participates in a wide array of
cellular activities, ranging from the cargo transport of proteins, RNA, and vesicles to nuclear migration
and cell division. Processive movement of dynein along microtubules requires the binding to the
essential co-activator dynactin and specific adaptor proteins, which recruit cargo and facilitate movement
by forming a stable ternary complex with dynein and dynactin. Our understanding of these interactions is
limited and many questions remain: How do cargo adaptors bring dynein and dynactin together? How
does this lead to activation of the motor and the initiation of transport? Which elements determine the
adaptor specificity? How do the disease-causing mutations modify these interactions? Importantly, it is
becoming increasingly evident that binding to light intermediate chain of dynein 1 (`LIC1') is a common
feature of functionally distinct adaptors. We will focus our investigations on the interaction between the
C-terminal tail of the LIC1 with the adaptors Spindly, BICD2 and Hook3, which each have important but
distinct functions in transport. These studies are complicated by the fact that the disordered nature of C-
terminal LIC1 makes it difficult to obtain a comprehensive dynamic view at atomic resolution from X-ray
or EM techniques. However, we will take the innovative approach of using nuclear magnetic resonance
(NMR) as a nano-scale `magnifying glass' that pinpoints interaction sites within the proteins at atomic
resolution. Compared to other methods, NMR is uniquely suited to study disordered proteins and to
characterize highly dynamic interactions. We propose four aims: (1) Structural and dynamical
characterization of free C-terminal dynein LIC1. (2) Characterization of dynein LIC1 interaction with
Spindly, BicD2 and Hook3, and their binding competition. (3) Prediction and testing of effects of
mutations on dynein LIC1 - adaptor interaction. (4) Structural & dynamic basis of interaction triangle
between dynein LIC1, Spindly and ROD/Zw10/Zwilch complex. Our experiments are therefore expected
to provide detailed molecular insight into how human dynein LIC1 engages with structurally diverse
dynein adaptors. Through collaboration, we will extend our findings into animal models. Overall, this
research is significant because the presence of pathogenic point mutations in dynein and adaptor
proteins suggests that these insights will also help to understand the diseases caused by malfunction of
the dynein-driven cargo transport and will offer therapeutic intervention targets.

## Key facts

- **NIH application ID:** 9993594
- **Project number:** 5R01GM130694-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Beat Rolf Vogeli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $325,082
- **Award type:** 5
- **Project period:** 2019-08-09 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993594

## Citation

> US National Institutes of Health, RePORTER application 9993594, Dynein-adaptor interaction mechanisms and malfunction at atomic resolution (5R01GM130694-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9993594. Licensed CC0.

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