Determining the dynein-dynactin complex structure: an interview with Dr Gabriel C. Lander

Dr. Gabriel LanderTHOUGHT LEADERS SERIES...insight from the world’s leading experts

What is the dynein-dynactin complex and where is it found? What functions is this molecular motor thought to perform within cells?

This is a macromolecular assembly is made up of two components, dynein and dynactin, that works to move molecular cargo (organelles, RNA, vesicles, proteins, viruses) along microtubule highways within our cells.

This complex is found within the cytoplasm of all cells, playing key roles in cell division, organelle positioning, and in clearing misfolded or aggregated proteins from cells.

Dynein is a dimeric molecule made up of two copies of six different protein subunits, with motor domains that attach to the microtubule surface via long stalks.

While dynein alone can attach to microtubules, it only gains the ability to move along the microtubule when it attaches to dynactin, a similarly sized multiprotein complex that also contains a microtubule-interacting region.

Interestingly, this combined assembly can only move in a single direction along microtubules, referred to as “retrograde” motion. However, the mechanism describing this dynactin-mediated regulation of motility, as well as its unidirectionality, is unknown.

In addition to dynactin, dynein also binds a variety of other adaptor proteins within the cell to accommodate interactions with different types of cargo.

What diseases have problems with the dynein-dynactin motor system been associated with?

While all cells contain the dynein-dynactin complex, the cells that are perhaps most dependent on proper function of this complex are neurons. Neuronal axons can extend to up to a meter in length in humans, and molecular motors play a critical role in maintaining their healthy function.

Mutations in dynein can lead to serious axonal defects, resulting in diseases such as spinal muscular atrophy and spino-bulbar muscular atrophy.

Also, the fact that the dynein-dynactin complex is heavily involved in mitotic division during brain development has implicated mutations in dynein or its associated cofactors in a number of neurodevelopmental diseases, the most notable being extreme microcephaly and lissencephaly.

Additionally, there is considerable evidence that disruptions of the dynein-dynactin system can cause a range of neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's, and Charcot-Marie-Tooth disease.

Since the retrograde motion of dynein-dynactin directs cargo to the core of the cell, viruses like HIV, herpes, and rabies have evolved to utilize the dynein-dynactin transport system to travel from the cellular periphery to the nucleus in order to hijack the cellular machinery for propagation.

Why have structural studies of the complex been restricted to small pieces of the whole up until now?

The many components of dynein assemble in to a large flexible structure that doesn't have a single defined conformation. Presumably, this flexibility enables the dynein to interact with a variety of different cargo and cofactor, as it moves along microtubules.

However, structural investigation generally requires conformational stability and homogeneity, and for this reason previous studies have only focused on the individual stable pieces of the complex, rather than examining the whole assembly.

What imaging and processing techniques did you use? How did you create a picture of the whole dynein-dynactin structure?

A combination of low-resolution and high-resolution electron microscopy imaging was employed to observe this complex. Electron microscopy is the only type of imaging that enables one to directly visualize the molecular details of such tiny flexible protein assemblies.

Due to the conformational heterogeneity of the complex, we had to acquire thousands of images of the complex, and then develop image processing programs that could focus on the individual components of dynein and dynactin.

By identifying the structural features that were consistent between all the thousands of images, we were able to significantly improve the resolution of the images, enabling us to decipher the molecular architecture of the complex.

What insights will this picture provide and will this research help to understand how defects in this system have been linked to diseases such as Huntington's, Parkinson's, and Alzheimer's?

This study provides the first snapshot of what this cargo transporter looks like as it walks along the microtubule lattice.

These findings provide a structural framework for understanding dynein-dynactin-mediated cargo transport, and for interpreting decades of biophysical and biochemical work aimed at decrypting the mechanics of dynein motor.

With these data in hand, we can begin to develop molecular models describing how known disease-causing mutations can potentially influence the inter-molecular interactions that establish this assembly.

Although this study significantly advances our understanding how the pieces of the puzzle come together, this is a first fundamental step in untangling the inner workings of the system, and many questions remain unanswered.

What further research is needed to fully understand the dynein-dynactin complex's role within cells?

There is much have yet to discover about this transport system, scientists at our institute and around the globe are probing the different aspects of the dynein-dynactin complex to better understand how dynein and dynactin function in the cellular environment.

The images we presented in our study show how the pieces come together, but a number of key questions need to be answered: Do many copies of this complex work together to haul cargo? How many? How are they turned on and off? How is their movement influenced by other regulatory cofactors? How are these machines loaded onto the microtubules?

We also still don't have a clear understanding of how energy consumption by the motor domains is translated into movement. Answering these questions will require data that go far beyond the structural information that we can provide, and will involve the combined results of studies that employ a range of biophysical, biochemical, and genetic approaches.

What are your research plans for the future?

We now know what this motor looks like when it's attached to the microtubule surface, but these complexes were lacking cargo.

We plan to build on the findings of this study to explore how this machine carries large enormous vesicles and organelles, as well as the protein aggregates found in the neurons of Alzheimer's and Parkinson's patients, microns in distance along the cellular interior.

These studies will require us to develop new biological and technical platforms to structurally characterize these complicated organizations, and data processing will involve the implementation of novel image processing algorithms.

In the coming years, we hope to establish a holistic understanding of the underlying mechanisms that drive this fascinating transporter complex.

Where can readers find more information?

Google is a great place to find out what labs are pursuing studies on dynein, dynactin, and cargo transport.

About Dr Gabriel C. Lander

Gabriel Lander is assistant professor of structural biology at The Scripps Research Institute, in La Jolla, California. He received his B.S. in biochemistry from Binghamton University, where he was recognized for his computational work with microtubules.

During his graduate studies at The Scripps Research Institute, he became fascinated with electron microscopy, using it to explore the structural rearrangements that virus proteins undergo during maturation.

During this time, Gabriel also spent much time developing software to streamline the analysis of single-particle cryo-electron microscopy (cryoEM) data, which is now in use by numerous labs around the world.

As a postdoc in the lab of Dr. Eva Nogales at UC Berkeley, he applied his cryoEM methodologies to investigate the properties of microtubule dynamics, contributing significantly to our understanding of the conformational cycles that accompany tubulin polymerization and catastrophe.

Gabriel also worked with the Andreas Martin lab to study the mechanism of protein degradation by the 26S proteasome, shedding light on the subunit architecture and molecular motions that dictate its function.

The Lander laboratory is currently interested in probing the molecular mechanisms that trigger the onset of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's.

Specifically, the lab is focused on understanding two cellular processes that are critical in keeping neurons free of dangerous protein aggregates – protein degradation through the ubiquitin-proteasome system, and microtubule-based cargo transport.

Using cryoEM, the Lander lab is working to solve the structures of the macromolecular machines that are involved in keeping neurons healthy, in order to better understand how disruptions in these systems lead to lethal misfolding and accumulation of polypeptides.

April Cashin-Garbutt

Written by

April Cashin-Garbutt

April graduated with a first-class honours degree in Natural Sciences from Pembroke College, University of Cambridge. During her time as Editor-in-Chief, News-Medical (2012-2017), she kickstarted the content production process and helped to grow the website readership to over 60 million visitors per year. Through interviewing global thought leaders in medicine and life sciences, including Nobel laureates, April developed a passion for neuroscience and now works at the Sainsbury Wellcome Centre for Neural Circuits and Behaviour, located within UCL.

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