Alzheimer's, Parkinson's, ALS: Scientists reveal structural secrets of nature's little locomotive

A team led by scientists at The Scripps Research Institute has determined the basic structural organization of a molecular motor that hauls cargoes and performs other critical functions within cells. The complex's large size, myriad subunits and high flexibility have until now restricted structural studies to small pieces of the whole.

Credit: Image courtesy of the Lander lab, The Scripps Research Institute.

Date:

March 9, 2015

Source:

Scripps Research Institute

Summary:

Scientists have determined the basic structural organization of a molecular motor that hauls cargoes and performs other critical functions within cells. The complex's large size, myriad subunits and high flexibility have until now restricted structural studies to small pieces of the whole.

A team led by scientists at The Scripps Research Institute (TSRI) has determined

the basic structural organization of a molecular motor that hauls cargoes and 

performs other critical functions within cells.

Biologists have long wanted to know how this molecular motor -- called the 

"dynein-dynactin complex" -- works. But the complex's large size, myriad 

subunits and high flexibility have until now restricted structural studies to small 

pieces of the whole.

In the new research, however, TSRI biologist Gabriel C. Lander and his 

laboratory, in collaboration with Trina A. Schroer and her group at Johns Hopkins 

University, created a picture of the whole dynein-dynactin structure.

"This work gives us critical insights into the regulation of the dynein motor and

 establishes a structural framework for understanding why defects in this system

 have been linked to diseases such as Huntington's, Parkinson's, and

 Alzheimer's," said Lander.

The findings are reported in a Nature Structural & Molecular Biology advance

online publication on March 9, 2015.

Unprecedented Detail

The proteins dynein and dynactin normally work together on microtubules for 

cellular activities such as cell division and intracellular transport of critical cargo

 such as mitochondria and mRNA. The complex also plays a key role in neuronal 

development and repair, and problems with the dynein-dynactin motor system 

have been found in brain diseases including Alzheimer's, Parkinson's and

 Huntington's diseases, and amyotrophic lateral sclerosis (ALS). In addition,

 some viruses (including herpes, rabies and HIV) appear to hijack the dynein-

dynactin transport system to get deep inside cells.

"Understanding how dynein and dynactin interact and work, and how they 

actually look, is definitely going to have medical relevance," said Research

 Associate Saikat Chowdhury, a member of the Lander lab who was first author of 

the study.

To study the dynein-dynactin complex, Schroer's laboratory first produced 

individual dynein and dynactin proteins, which are themselves complicated, with

 multiple subunits, but have been so highly conserved by evolution that they are 

found in almost identical form in organisms from yeast to mammals.

Chowdhury and Lander then used electron microscopy (EM) and cutting-edge 

image-processing techniques to develop two-dimensional "snapshots" of dynein's

 and dynactin's basic structures. These structural data contained unprecedented

 detail and revealed subunits never observed before.

Chowdhury and Lander next developed a novel strategy to purify and image 

dynein and dynactin in complex together on a microtubule -- a railway-like

 structure, ubiquitous in cells, along which dynein-dynactin moves its cargoes.

"This is the first snapshot of how the whole dynein-dynactin complex looks and 

how it is oriented on the microtubule," Chowdhury said.

Pushing the Limits

The structural data clarify how dynein and dynactin fit together on a microtubule,

 how they recruit cargoes and how they manage to move those cargoes

 consistently in a single direction.

Lander and Chowdhury now hope to build on the findings by producing a higher-

resolution, three-dimensional image of the dynein-dynactin-microtubule complex, 

using an EM-related technique called electron tomography.

"The EM facility at TSRI is the best place in the world to push the limits of

 imaging complicated molecular machines like these," said Lander.

The research was supported by the Damon Runyon Cancer Research Foundation 

(DFS-#07-13), the Pew Scholars program, the Searle Scholars program and the

 National Institutes of Health (DP2 EB020402-01, GM44589).

Story Source:

The above story is based on materials provided by Scripps Research Institute. Note: Materials may be edited for content and length.

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Journal Reference:

1. Saikat Chowdhury, Stephanie A Ketcham, Trina A Schroer, Gabriel C Lander. Structural organization of the dynein–dynactin complex bound to microtubules. Nature Structural & Molecular Biology, 2015; DOI: 10.1038/nsmb.2996

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Scripps Research Institute. "Alzheimer's, Parkinson's, ALS: Scientists reveal structural secrets of nature's little locomotive." ScienceDaily. ScienceDaily, 9 March 2015. <www.sciencedaily.com/releases/2015/03/150309160614.htm>.

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