Corporate Banner
Satellite Banner
Crystallography
Scientific Community
 
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 2,400+ scientific posters on ePosters
  • More than 3,700+ 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

Scripps Research Institute Scientists Capture Picture of 'MicroRNA' in Action
The Findings Will Help Guide Drug Design.
Thursday, October 30, 2014
Scripps Researchers Find New Point of Attack on HIV for Vaccine Development
The newly identified site can be attacked by human antibodies in a way that neutralizes the infectivity of a wide variety of HIV strains.
Friday, April 25, 2014
Scripps Research Institute Study Finds New Moves in Protein's Evolution
Findings point to new approach to drug design.
Monday, October 07, 2013
Study Reveals How Serotonin Receptors Can Shape Drug Effects from LSD to Migraine Medication
A team of scientists has determined and analyzed the high-resolution atomic structures of two kinds of human serotonin receptor.
Tuesday, March 26, 2013
Scripps Research Scientists find E. Coli Enzyme must move to Function
Slight oscillations lasting just milliseconds have a huge impact on an enzyme's function, according to a new study by Scripps Research Institute scientists.
Monday, April 18, 2011
Scripps Research Scientists Solve Protein Structure Revealing Secrets of Cell Membranes
The Findings May Lead to Better Methods to Deliver Drugs
Thursday, May 06, 2010
Scripps Scientists Uncover Mimicry at the Molecular Level that Protects Genome Integrity
Study draws new parallels between the Rad60 DNA repair factor and SUMO; both essential for maintaining genome stability during replication.
Wednesday, April 15, 2009
Scientists Create First Crystal Structure of an Intermediate Particle in Virus Assembly
A research team at the Scripps Research Institute has been able to produce the first crystal structure of a virus particle caught in the midst of assembling its impenetrable outer protein coat.
Monday, March 23, 2009
Scientific News
TOPLESS Plants Provide Clues to Human Molecular Interactions
Scientists at Van Andel Research Institute have revealed an important molecular mechanism in plants that has significant similarities to certain signaling mechanisms in humans, which are closely linked to early embryonic development and to diseases such as cancer.
Advancing Cancer Drug Design with Image of Key Protein
Scientists have pioneered the use of a high-powered imaging technique to picture in exquisite detail one of the central proteins of life – a cellular recycling unit with a role in many diseases.
Mould Unlocks New Route to Biofuels
Scientists at The University of Manchester have made an important discovery that forms the basis for the development of new applications in biofuels and the sustainable manufacturing of chemicals.
'Invisible' Protein Structure Explains the Power of Enzymes
A research group at Umeå University in Sweden has managed to capture and describe a protein structure that, until now, has been impossible to study.
Unraveling the Elusive Structure of HIV Protein
Snapshots of HIV virus’ proteins may help design new ways to fight the disease.
Blueprinting Cell Membrane Proteins
Recent breakthrough will make the blueprinting process faster, easier and cheaper, and should have major implications in the field of drug discovery and development.
Bacteria Use Chemical Harpoons to Hold on Their Hosts
Researchers reveal how a common disease causing bacteria latches on to the body during an infection.
Solving Streptide from Structure to Biosynthesis
Researchers reveal new information about how bacteria communicate via the protein, streptide.
Near-Atomic Resolution of Protein Structure Holds Promise for Drug Discovery
A new study shows that it is possible to use an imaging technique called cryo-electron microscopy to view the architecture of a metabolic enzyme bound to a drug that blocks its activity.
X-ray Study May Aid in Designing Better Blood Pressure Drugs
New atomic-scale details could help create more effective medications with fewer side effects.
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
2,400+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!