Activate Now
 
ProHealth health Vitamin and Natural Supplement Store and Health
Home  |  Log In  |  My Account  |  View Cart  View Your ProHealth Vitamin and Supplement Shopping Cart
800-366-6056  |  Contact Us  |  Help
Facebook Google Plus
Fibromyalgia  Chronic Fatigue Syndrome & M.E.  Lyme Disease  Natural Wellness  Supplement News  Forums  Our Story
Store     Brands   |   A-Z Index   |   Best Sellers   |   New Products   |   Deals & Specials   |   Under $10   |   SmartSavings Club

Trending News

Patient Insights into the Design of Technology to Support a Strengths-Based Approach to Health Care.

Greater intake of dietary omega-3 fatty acids associated with lower risk of diabetic retinopathy

SURVEY: Weight Management & Chronic Illness

Japanese green tea consumers have reduced risk of dementia

Researchers find herpes strain in the nervous system

Do Nothing, Accomplish Everything! The Connection Between Breathing and Healing

Nature Heals

Best Herbs to Help With Insomnia

Meet the ProHealth Editors

Choline: Why You Should Eat Your Egg Yolks and Take Krill

 
Print Page
Email Article

Scripps Research Scientists Solve Structure of a Critical Innate Immune System Protein

  [ 63 votes ]   [ Discuss This Article ]
www.ProHealth.com • June 22, 2005


La Jolla, CA, June 20, 2005—Scientists at The Scripps Research Institute have solved the structure of a crucial human immune system molecule called TLR3, an acronym for Toll-like receptor three. In an upcoming issue of the journal Science, the protein is described as a large horseshoe-shaped coil composed of 23 leucine-rich repeats (LRRs). The structure reveals details of TLR3 that have never been seen before, an essential step toward fully understanding the critical role this protein—and other TLRs—play in the human innate immune system to rapidly detect invading pathogens. "We don't know functionally how TLR proteins work," says Professor Ian Wilson, D.Phil., who is a professor in the Department of Molecular Biology at The Scripps Research Institute and a member of The Skaggs Institute for Chemical Biology. "But the structure has given us great insights into experiments we can design to explore their function. In advance, we wouldn't have known where to look." In addition to helping scientists better understand how TLRs work, the structure may also help scientists take steps toward improving human health, since TLRs are implicated in a number of diseases and, hence, constitute potential therapeutic targets. Innate Immunity and Toll-Like Receptors Humans, like all other organisms, are constantly challenged in a world filled with microbial pathogens. We are bathed in bacteria, confronted with fungi, pilloried with parasites, and invaded by viruses. And yet, most of the time, we survive. We survive because we possess an ancient and crucial defense mechanism known as innate immune system, which is active in eukaryotic organisms as diverse as humans and fruit flies. Broadly speaking, the innate immune system works something like this. Certain cells have the ability to recognize foreign molecules such as components of membrane like LPS or other protein molecules unique to microorganisms. The presence of these pathogen-specific molecules activates the immune system, which responds with a multi-stage biochemical defense starting with the unleashing of an army of white blood cells, like macrophages, which engulf and destroy pathogens. The macrophages also fight the pathogens by producing large amounts of chemicals that induce inflammation and help the body clear the infection. One of the components of the innate immune system that scientists have been studying for the last several years is a family of receptor proteins called the Toll-like receptors (TLR)—a name that comes from their resemblance to a fruit fly receptor called "Toll." In the fly, Toll is important for both embryonic development and for immune functions of the adult organism. In adult fruit flies, the protein is an essential receptor molecule that defends against fungal infections. In humans, TLRs play a critical role in the immune system because they are the molecules responsible for detecting some of the antigens produced by pathogens. For this reason, Toll-like receptors have been called the eyes of the innate immune system. Normally, when human or mouse cells encounter bacteria or viruses, they recognize proteins, lipids, or other molecular components of these foreign invaders through a family of TLR proteins, and then trigger the immune system's multi-stage biochemical attack on the pathogens. Humans have at least 10 different TLRs, each of which recognizes a specific subset of antigens. For instance, TLR4 recognizes lipopolysaccharide, a chemical component of the cell walls of certain bacteria like Neisseria meningitides—one of the leading causes of bacterial meningitis. TLR9 recognizes bacterial DNA that contains distinguishing CpG dinucleotides motifs. TLR3 in Detail Likewise, TLR3 recognizes double-stranded RNA, which is the form of genetic information carried by many viruses. The structure that Wilson and his colleagues have solved shows how the repeating leucine-rich repeat motifs assembled in TLR3 in never-before-seen detail. The portion of TLR3 the scientists solved lies on the outside of the membrane and reveals the potential binding site for its ligand, double-stranded RNA. TLR3 forms a large horseshoe shape that contacts with a neighboring horseshoe, forming a "dimer" of two horseshoes. Much of the TLR3 protein surface is covered with sugar molecules, but on one face that includes the interface between these two horseshoes, there is a large surface that is sugar-free, suggesting that this is where the TLR3 might bind to its target molecule. This surface also contains two distinct patches that are rich in positively-charged residues, suggesting it as a possible binding site for negatively-charged double-stranded RNA. "It's a sensational piece of work," says Scripps Research Professor Bruce Beutler, M.D., who studies TLR signaling together with his group in the TSRI Department of Immunology. "All of us in the TLR field have been dying to see the structure of a TLR ectodomain since the innate immune function of TLRs was discovered seven years ago. This will open the way to a great many other studies that will allow us to understand exactly how signaling occurs." Significantly, says Wilson, the structure is also another milestone of sorts. These membrane-spanning proteins are rich in repeats that contain a high percentage of the amino acid leucine. This fact was important to Wilson and his colleagues because the leucine-rich proteins are often decorated with sugars (glycans), and fall into the class of biological molecules known as "glycoproteins." "Amazingly there is still this prevalent idea [many scientists have] that glycoproteins don't crystallize," says Wilson. Crystallization of a protein is a crucial initial step in solving its structure via x-ray crystallography, the technique that Wilson and his colleagues employ. Because glycoproteins are covered with sugars, they are heterogenous due to the multiple glycoforms that make it harder, but not impossible, to form good crystals. A number of leucine-rich repeat proteins have been determined, but never one with this many leucine-rich repeats or so many carbohydrates. The article, "Crystal structure of human Toll-like receptor 3 (TLR3) ectodomain" is authored by Jungwoo Choe, Matthew S. Kelker, and Ian A. Wilson and is being published in SCIENCE EXPRESS, the early online publication site of the journal Science. See: http://www.sciencemag.org. The article will also appear in print in an upcoming issue of Science. This work was supported by the National Institutes of Health and The Skaggs Institute for Research. About The Scripps Research Institute and Scripps Florida The Scripps Research Institute in La Jolla, California, and Palm Beach County, Florida, is one of the world's largest, independent, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. The Scripps Research Institute employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel in 14 buildings overlooking the Pacific Ocean in La Jolla, a part of the City of San Diego. Scripps Florida will be a 350,000 square-foot, state-of-the-art biomedical research facility to be built on 100 acres of undeveloped land in Palm Beach County. Scripps Florida will focus on basic biomedical science, drug discovery, and technology development, employing more than 500 researchers and support staff by 2010. Palm Beach County and the State of Florida have provided start-up economic incentives for development, building, staffing, and equipping the campus. Scripps Florida is now operating with more than 100 researchers and technicians at a 40,000 square-foot facility on the campus of Florida Atlantic University in Jupiter. Source: The Scripps Research Institute



Post a Comment

Featured Products From the ProHealth Store
Optimized Curcumin Longvida® FibroSleep™ Ultra ATP+, Double Strength

Looking for Vitamins, Herbs and Supplements?
Search the ProHealth Store for Hundreds of Natural Health Products


Article Comments



Be the first to comment on this article!

Post a Comment


 
Natural Pain Relief Supplements

Featured Products

Ultra ATP+, Double Strength Ultra ATP+, Double Strength
Get energized with malic acid & magnesium
Mitochondria Ignite™ with NT Factor® Mitochondria Ignite™ with NT Factor®
Reduce Fatigue up to 45%
FibroSleep™ FibroSleep™
The All-in-One Natural Sleep Aid
Ultra EPA  - Fish Oil Ultra EPA - Fish Oil
Ultra concentrated source of essential fish oils
Energy NADH™ 12.5mg Energy NADH™ 12.5mg
Improve Energy & Cognitive Function

Natural Remedies

When a Negative is Positive - Goodnighties Recovery Sleepwear When a Negative is Positive - Goodnighties Recovery Sleepwear
How Glutathione Can Save Your Life How Glutathione Can Save Your Life
Live Without Anxiety or Stress Live Without Anxiety or Stress
Strengthen Cell Function with Energy-Boosting Niagen Strengthen Cell Function with Energy-Boosting Niagen
Stop Bacteria With Nature's Antibiotics Stop Bacteria With Nature's Antibiotics

CONTACT US
ProHealth, Inc.
555 Maple Ave
Carpinteria, CA 93013
(800) 366-6056  |  Email

· Become a Wholesaler
· Vendor Inquiries
· Affiliate Program
SHOP WITH CONFIDENCE
Credit Card Processing
SUBSCRIBE AND SAVE 15% NOW*
Be the first to know about new products, special discounts and the latest health news. *New subscribers only

CONNECT WITH US ProHealth on Facebook  ProHealth on Twitter  ProHealth on Pinterest  ProHealth on Google Plus

© 2016 ProHealth, Inc. All rights reserved. Pain Tracker App  |  Store  |  Customer Service  |  Guarantee  |  Privacy  |  Contact Us  |  Library  |  RSS  |  Site Map