Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Scripps Research Institute Scientists Find the Structure of a Key ‘Gene Silencer’ Protein

Published: Monday, April 30, 2012
Last Updated: Monday, April 30, 2012
Bookmark and Share
The structure reveals potential therapeutic targets in area with ‘untapped potential’.

Scientists at The Scripps Research Institute have determined the three-dimensional atomic structure of a human protein that is centrally involved in regulating the activities of cells. Knowing the precise structure of this protein paves the way for scientists to understand a process known as RNA-silencing and to harness it to treat diseases.

“Biologists have known about RNA-silencing for only a decade or so, but it’s already clear that there’s an enormous untapped potential here for new therapies,” said Ian MacRae, an assistant professor at Scripps Research and senior author of the new report.

The new report, which appeared on April 26, 2012 in the journal Science’s advance online publication, Science Express, focuses on Argonaute2. This protein can effectively “silence” a gene by intercepting and slicing the gene’s RNA transcripts before they are translated into working proteins.

Interception and Destruction of Messages

When a gene that codes for a protein is active in a cell, its information is transcribed from DNA form into lengths of nucleic acid called messenger RNA (mRNA). If all goes well, these coded mRNA signals make their way to the cell’s protein-factories, which use them as templates to synthesize new proteins. RNA-silencing, also called RNA interference (RNAi), is the interception and destruction of these messages—and as such, is a powerful and specific regulator of cell activity, as well as a strong defender against viral genes.

The silencing process requires not only an Argonaute protein but also a small length of guide RNA, known as a short-interfering RNA or microRNA. The guide RNA fits into a slot on Argonaute and serves as a target recognition device. Like a coded strip of VelcroTM, it latches onto a specific mRNA target whose sequence is the chemical mirror image, or “complement,” of its own—thus bringing Argonaute into contact with its doomed prey.

Argonaute2 is not the only type of human Argonaute protein, but it seems to be the only one capable of destroying target RNA directly. “If the guide RNA is completely complementary to the target RNA, Argonaute2 will cleave the mRNA, and that will elicit the degradation of the fragments and the loss of the genetic message,” said Nicole Schirle, the graduate student in MacRae’s laboratory who was lead author of the paper.

Aimed at disease-causing genes or even a cell’s own overactive guide RNAs, RNA-silencing could be a powerful therapeutic weapon. In principle, one needs only to inject target-specific guide RNAs, and these will link up with Argonaute proteins in cells to find and destroy the target RNAs. Scientists have managed to do this successfully with relatively accessible target cells, such as in the eye. But they have found it difficult to develop guide RNAs that can get from the bloodstream into distant tissues and still function.

“You have to modify the guide RNA, in some way to get it through the blood and into cells, but as soon as you start modifying it, you disrupt its ability to interact with Argonaute,” said MacRae. Knowing the precise structure of Argonaute should enable researchers to clear this hurdle by designing better guide RNA.

More Points for Manipulation

Previous structural studies have focused mostly on Argonaute proteins from bacteria and other lower organisms, which have key differences from their human counterparts. Schirle was able to produce the comparatively large and complex human Argonaute2 and to manipulate it into forming crystals for X-ray crystallography analysis—a feat that structural biologists have wanted to achieve for much of the past decade. “It was just excellent and diligent crystallography on her part,” said MacRae.

The team’s analysis of Argonaute2’s structure revealed that it has the same basic set of working parts as bacterial Argonaute proteins, except that they are arranged somewhat differently. Also, key parts of Argonaute2 have extra loops and other structures, not seen on bacterial versions, which may play roles in binding to guide RNA. Finally, Argonaute2 has what appear to be binding sites for additional co-factor proteins that are thought to perform other destructive operations on the target mRNA.

“Basically, this Argonaute protein is more sophisticated than its bacterial cousins; it has more bells and whistles, which give us more points for manipulation. With this structure solved, we no longer need to use the prokaryotic structures to guess at what human Argonaute proteins look like,” MacRae said.
He and Schirle and others in the lab now are analyzing the functions of Argonaute2’s substructures, as well as looking for ways to design better therapeutic guide RNAs.

“Now with the structural data, we can see what synthetic guide RNAs will work with Argonaute and what won’t,” MacRae said. “We might even be able to make guide RNAs that can outcompete natural ones.”
The research that led to Schirle and MacRae’s new paper, “The Crystal Structure of Human Argonaute2,” was funded by the National Institute of General Medical Sciences, part of the National Institutes of Health.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,000+ scientific posters on ePosters
  • More Than 4,500+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Breakthrough Approach to Breast Cancer Treatment
Scripps scientists have designed a drug candidate that decreases growth of breast cancer cells.
Tuesday, May 24, 2016
Making Genetic Data Easier to Search
Scripps team streamlines biomedical research by making genetic data easier to search.
Tuesday, May 17, 2016
Potent Therapeutic 'Warheads' That Target Cancer Cells
Scripps scientists have developed molecular “warheads” that could be used to treat cancer.
Tuesday, May 17, 2016
Predicting Cell Changes that Affect Breast Cancer Growth
Researchers find small structural changes in a key breast cancer receptor that can predict cancer growth.
Tuesday, May 03, 2016
Secrets of a Deadly Virus Family Revealed
Scripps Research scientists uncover the glycoprotein structure of LCMV. The findings could guide development of treatments for Lassa fever.
Wednesday, April 27, 2016
First ‘Teenage’ HIV-Neutralizing Antibody Discovered
Scientists have studied the evolution of anti-HIV antibodies, with hopes of creating a vaccine to prevent AIDS.
Wednesday, April 06, 2016
Discovering 'Outlier' Enzymes
Researchers at TSRI and Salk Institute have discovered 'Outlier' enzymes that could offer new targets to treat type 2 diabetes and inflammatory disorders.
Saturday, April 02, 2016
Encouraging Foundation for Upcoming AIDS Vaccine Clinical Trial
Engineered vaccine protein binds key immune cells that exist in nearly everyone.
Tuesday, March 29, 2016
New Approach to Curbing Cancer Cell Growth
Using a new approach, scientists at The Scripps Research Institute (TSRI) and collaborating institutions have discovered a novel drug candidate that could be used to treat certain types of breast cancer, lung cancer and melanoma.
Monday, March 14, 2016
Vaccine Against Dangerous Designer Opioids
With use of synthetic opioid "designer drugs" on the rise, scientists from The Scripps Research Institute (TSRI) have a new strategy to curb addiction and even prevent fatal overdoses.
Thursday, February 18, 2016
Potential Target for Treatment of Autism
Grant of $2.4 million will support further research.
Friday, October 02, 2015
Key Morphine Regulator Identified
The findings could lead to less addictive pain medications.
Thursday, September 24, 2015
$6 Million Awarded to Develop Alternative HIV/AIDS Vaccine
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded up to nearly $6 million from the Bill & Melinda Gates Foundation to develop a revolutionary HIV/AIDS alternative vaccine that has demonstrated great potential in animal models.
Thursday, September 24, 2015
Novel Role of Mitochondria in Immune Function Identified
Scientists at The Scripps Research Institute (TSRI) have discovered a new role for an enzyme involved in cell death.
Monday, September 21, 2015
Scientists Make Strides in Therapy Preventing Addiction Relapse
Single Injection of Drug Candidate Prevents Meth Relapse in Animal Models.
Thursday, August 06, 2015
Scientific News
The Rise of 3D Cell Culture and in vitro Model Systems for Drug Discovery and Toxicology
An overview of the current technology and the challenges and benefits over 2D cell culture models plus some of the latest advances relating to human health research.
Scientists Find Evidence That Cancer Can Arise Changes
Researchers at Rockefeller University have found a mutation that affects the proteins that package DNA without changing the DNA itself can cause a rare form of cancer.
Developing a More Precise Seasonal Flu Vaccine
During the 2014-15 flu season, the poor match between the virus used to make the world’s vaccine stocks and the circulating seasonal virus yielded a vaccine that was less than 20 percent effective.
A Peachy Defense System for Seeds
ETH chemists are developing a new coating method to protect seeds from being eaten by insects. In doing so, they have drawn inspiration from the humble peach and a few of its peers.
Fighting Cancer with Borrowed Immunity
A new step in cancer immunotherapy: researchers from the Netherlands Cancer Institute and University of Oslo/Oslo University Hospital show that even if one's own immune cells cannot recognize and fight their tumors, someone else's immune cells might.
Modified Microalgae Converts Sunlight into Valuable Medicine
A special type of microalgae can soon produce valuable chemicals such as cancer treatment drugs and much more just by harnessing energy from the sun.
Breakthrough Approach to Breast Cancer Treatment
Scripps scientists have designed a drug candidate that decreases growth of breast cancer cells.
Loss Of Y Chromosome Increases Risk Of Alzheimer’s
Men with blood cells that do not carry the Y chromosome are at greater risk of being diagnosed with Alzheimer’s disease. This is in addition to an increased risk of death from other causes, including many cancers. These new findings by researchers at Uppsala University could lead to a simple test to identify those at risk of developing Alzheimer’s disease.
Making Virus Sensors Cheap and Simple
Researchers at The University of Texas at Austin demonstrated the ability to detect single viruses in a solution containing murine cytomegalovirus (MCMV).
A Guide to CRISPR Gene Activation
A comparison of synthetic gene-activating Cas9 proteins can help guide research and development of therapeutic approaches.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,500+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!