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
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 2,500+ scientific posters on ePosters
  • More Than 3,800+ 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

Scientists Make Strides in Therapy Preventing Addiction Relapse
Single Injection of Drug Candidate Prevents Meth Relapse in Animal Models.
Thursday, August 06, 2015
New Antibody Weapons Against Marburg Virus
A study has identified new immune molecules that protect against deadly Marburg virus, a relative of Ebola virus.
Tuesday, June 30, 2015
Team Led by TSRI Scientists Shows AIDS Vaccine Candidate Successfully ‘Primes’ Immune System
New research shows that an experimental vaccine candidate can stimulate immune activity necessary to prevent HIV infection.
Thursday, June 25, 2015
New Details of Potential Alzheimer’s Treatment Uncovered
Scientists from Florida’s Scripps Resarch Institute have uncovered suprising new details of potential Alzheimer’s treatment.
Wednesday, April 29, 2015
Search for Cancer Drug Candidates
Scripps Florida scientists awarded $1.2 million to find drug candidates that could treat a wide range of cancers.
Friday, April 10, 2015
Scripps Florida Scientists Win $1.5 Million Grant to Develop New Cancer Drugs
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded a $1.5 million grant from the National Institutes of Health (NIH) to develop drug candidates that could treat cancer and neurodegenerative disease.
Tuesday, March 24, 2015
Day-Night Cycles Linked to Mutations
TSRI scientists show that proteins critical in day-night cycles also protect cells from mutations.
Friday, March 13, 2015
More DNA & Extra Copies of Disease Gene in Alzheimer’s Brain Cells
Scientists at The Scripps Research Institute (TSRI) have found diverse genomic changes in single neurons from the brains of Alzheimer’s patients, pointing to an unexpected factor that may underpin the most common form of the disease.
Tuesday, February 24, 2015
Possible Neuron Killing Mechanism Behind Alzheimer’s and Parkinson’s Diseases Discovered
$1.4 million grant will enable team to follow up with search for drug candidates.
Tuesday, February 17, 2015
Microbes Prevent Malnutrition in Fruit Flies—and Maybe Humans, Too
Study shows that microbes play a critical role in nutritional disorders.
Friday, February 13, 2015
New Targets and Test to Develop Treatments for Memory Disorders
The study focuses on kinesin, a molecular motor protein that plays a role in the transport of other proteins throughout a cell.
Thursday, November 13, 2014
MS Drug Candidate Shows Promise for Ulcerative Colitis
Positive new clinical data were released today on a drug candidate for ulcerative colitis that was first discovered and synthesized at The Scripps Research Institute.
Thursday, October 30, 2014
New Technique has Profound Implications for Drug Development
The method, developed by Scripps Research Institute chemists, expands options for making pure batches of ‘one-handed’ molecules.
Thursday, October 30, 2014
Scripps Research Institute Scientists Capture Picture of 'MicroRNA' in Action
The Findings Will Help Guide Drug Design.
Thursday, October 30, 2014
Enzyme Could Help Explain Origins of Life
Mimicking natural evolution in a test tube, scientists at The Scripps Research Institute (TSRI) have devised an enzyme with a unique property that might have been crucial to the origin of life on Earth.
Wednesday, October 29, 2014
Scientific News
Health Risks of Saturated Fats Aggravated by Immune Response
Research shows that the presence of saturated fats resulted in monocytes migrating into the tissues of vital organs.
Changing the Biological Data Visualisation World
Scientists at TGAC, alongside European partners, have created a cutting-edge, open source community for the life sciences.
NIH Study Finds Calorie Restriction Lowers Some Risk Factors for Age-Related Diseases
Two-year trial did not produce expected metabolic changes, but influenced other life span markers.
Immunotherapy Agent Benefits Patients with Drug-Resistant Multiple Myeloma in First Human Trial
Daratumumab proved generally safe in patients, even at the highest doses.
Low-level Arsenic Exposure Before Birth Associated with Early Puberty in Female Mice
Study examine whether low-dose arsenic exposure could have similar health outcomes in humans.
Inciting an Immune Attack On Cancer Cells
A new minimally invasive vaccine that combines cancer cells and immune-enhancing factors could be used clinically to launch a destructive attack on tumors.
‘Mutation-Tracking’ Blood Test for Breast Cancer
Scientists have developed a blood test for breast cancer able to identify which patients will suffer a relapse after treatment, months before tumours are visible on hospital scans.
Cellular Contamination Pathway for Heavy Elements Identified
Berkeley Lab scientists find that an iron-binding protein can transport actinides into cells.
Intensity of Desert Storms May Affect Ocean Phytoplankton
MIT study finds phytoplankton are extremely sensitive to changing levels of desert dust.
Common ‘Heart Attack’ Blood Test May Predict Future Hypertension
Small rises in troponin levels may have value as markers for subclinical heart damage and high blood pressure.
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
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!