Science Current Events | Science News | Brightsurf.com
 

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

April 27, 2012

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.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. Over the past decades, Scripps Research has developed a lengthy track record of major contributions to science and health, including laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. The institute employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists-including three Nobel laureates-work toward their next discoveries. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

The Scripps Research Institute



More Gene Silencer Current Events and Gene Silencer News Articles

First Aid for the Usmle Step 1, 2016

First Aid for the Usmle Step 1, 2016
by Tao Le (Author), Vikas Bhushan (Author)


THE “BIBLE” FOR USMLE STEP 1 PREP―AND THE ULTIMATE TOOL FOR ORGANIZING YOUR STUDY!This annually updated review delivers a comprehensive collection of high-yield facts and mnemonics that pinpoint exactly what students need to know to pass the exam. Co-authored by medical students who recently took the boards, it provides a complete framework to help students prepare for the most stressful exam of their careers.1,250+ must-know topics provide a complete framework for your Step 1 preparationTest-taking advice with focus on high-efficiency studyingUpdated in all subject areas based on feedback from thousands of studentsExtensive faculty review process with nationally known USMLE instructors1,000+ color photos and diagrams help you visualize high-yield conceptsExpanded guide to top-rated...

Gene-Environment Interactions in Psychiatry: Nature, Nurture, Neuroscience

Gene-Environment Interactions in Psychiatry: Nature, Nurture, Neuroscience
by Bart Ellenbroek (Author), Ji Un Youn (Author)


Gene-Environment Interactions in Psychiatry: Nature, Nurture, Neuroscience begins with the basic aspects of gene-environment studies, such as basic genetics, principles of animals modeling, and the basic processes of how environmental factors affect brain and behavior, with part two describing the most important psychiatric disorders in detail. Each chapter has a similar structure that includes a general description of the disorder that is followed by an analysis of the role of genes and how they are affected by environmental factors. Each chapter ends with a description of the most relevant animal models, again focusing on gene-environment interactions. The book concludes with a critical evaluation of the current research and an outlook for the (possible) future, offering a vignette...

Data Mining for Genomics and Proteomics: Analysis of Gene and Protein Expression Data

Data Mining for Genomics and Proteomics: Analysis of Gene and Protein Expression Data
by Darius M. Dziuda (Author)


Data Mining for Genomics and Proteomics uses pragmatic examples and a complete case study to demonstrate step-by-step how biomedical studies can be used to maximize the chance of extracting new and useful biomedical knowledge from data. It is an excellent resource for students and professionals involved with gene or protein expression data in a variety of settings.

Mechanisms of Gene Regulation

Mechanisms of Gene Regulation
by Carsten Carlberg (Author), Ferdinand Molnár (Author)


This textbook aims to describe the fascinating area of eukaryotic gene regulation for graduate students in all areas of the biomedical sciences. Gene expression is essential in shaping the various phenotypes of cells and tissues and as such, regulation of gene expression is a fundamental aspect of nearly all processes in physiology, both in healthy and in diseased states. This pivotal role for the regulation of gene expression makes this textbook essential reading for students of all the biomedical sciences, in order to be better prepared for their specialized disciplines.A complete understanding of transcription factors and the processes that alter their activity is a major goal of modern life science research. The availability of the whole human genome sequence (and that of other...

Biology: Concepts and Applications without Physiology

Biology: Concepts and Applications without Physiology
by Cecie Starr (Author)


In the new edition of BIOLOGY: CONCEPTS AND APPLICATIONS, authors Cecie Starr, Christine A. Evers, and Lisa Starr have partnered with the National Geographic Society to develop a text designed to engage and inspire. This trendsetting text introduces the key concepts of biology to non-biology majors using clear explanations and unparalleled visuals. While mastering core concepts, each chapter challenges students to question what they read and apply the concepts learned, providing students with the critical thinking skills and science knowledge they need in life. Renowned for its writing style the new edition is enhanced with exclusive content from the National Geographic Society, including over 200 new photos and illustrations. New People Matter sections in most chapters profile National...

First Aid for the USMLE Step 1 2015

First Aid for the USMLE Step 1 2015
by Tao Le (Author), Vikas Bhushan (Author)


THE 25th EDITION OF THE WORLD'S MOST POPULAR MEDICAL REVIEW BOOK! Trust 25 years of experience for the most effective USMLE Step 1 preparation possible 1,250+ must-know topics provide a complete framework for your USMLE preparation Test-taking advice with focus on high-efficiency studying Major revisions in all subject areas based on feedback from thousands of students Free real-time updates and corrections at www.firstaidteam.com Extensive faculty review process with nationally known USMLE instructors 1,000+ color photos and diagrams help you visualize high-yield concepts Expanded guide to high-yield study resources, including mobile apps INSIDER ADVICE FOR STUDENTS FROM STUDENTS

Gene Therapy for Viral Infections

Gene Therapy for Viral Infections
by Patrick Arbuthnot (Author)


Gene Therapy for Viral Infections provides a comprehensive review of the broader field of nucleic acid and its use in treating viral infections. The text bridges the gap between basic science and important clinical applications of the technology, providing a systematic, integrated review of the advances in nucleic acid-based antiviral drugs and the potential advantages of new technologies over current treatment options.  Coverage begins with the fundamentals, exploring varying topics, including harnessing RNAi to silence viral gene expression, antiviral gene editing, viral gene therapy vectors, and non-viral vectors. Subsequent sections include detailed coverage of the developing use of gene therapy for the treatment of specific infections, the principles of rational design of...

Gene Expression: General and Cell-Type-Specific (Progress in Gene Expression)

Gene Expression: General and Cell-Type-Specific (Progress in Gene Expression)
by M. Karin (Editor)


This book is the first volume in a new series Progress in Gene Expres­ sion. The control of gene expression is a central-most topic in molecular biology as it deals with the utilization and regulation of gene informa­ tion. As we see huge efforts mounting all over the developed world to understand the structure and organization of several complex eukaryotic genomes in the form of Gene Projects and Genome Centers, we have to remember that without understanding the basic mechanisms that gov­ ern the use of genetic information, much of this effort will not be very productive. Fortunately, however, research during the past seven years on the mechanisms that control gene expression in eukaryotes has been extremely successful in generating a wealth of information on the basic strategies of...

Gene Regulatory Sequences and Human Disease

Gene Regulatory Sequences and Human Disease
by Nadav Ahituv (Editor)


In Gene Regulatory Sequences and Human Disease, the Editor will introduce the different technological advances that led to this breakthrough. In addition, several examples will be provided of nucleotide variants in noncoding sequences that have been shown to be associated with various human diseases.

Genes and Cardiovascular Function

Genes and Cardiovascular Function
by Bohuslav Ostadal (Editor), Makoto Nagano (Editor), Naranjan S. Dhalla (Editor)


Rapid advances in molecular medicine have led to pronounced new developments in experimental and clinical cardiology.  In the embrace of modern molecular biology and bridging the gap between the clinical and the genomic, cardiovascular medicine has seen major strides in the understanding of the molecular mechanisms that drive disease progression.  The ability to rapidly identify candidate human genes for cardiovascular diseases lends itself to the development of diverse strategies for disease treatment and management.  The wide variety of gene expressions proffers excellent targets for novel therapeutics.  Gene therapy is steadily increasing in viability and represents a fascinating arena of research and clinical focus. This book is based on two international Mendel symposia on...

© 2016 BrightSurf.com