Featured Research

from universities, journals, and other organizations

Structure Of Fat-Depleting Protein Reveals Important Functional Clues

Date:
March 19, 1999
Source:
Howard Hughes Medical Institute
Summary:
Following a mysterious crevice in a molecule that causes severe weight loss in some cancer patients may turn up a new generation of drugs to treat clinical obesity, say researchers from the Howard Hughes Medical Institute (HHMI) at the California Institute of Technology.

March 19, 1999 —- Following a mysterious crevice in a molecule that causes severe weight loss in some cancer patients may turn up a new generation of drugs to treat clinical obesity, say researchers from the Howard Hughes Medical Institute (HHMI) at the California Institute of Technology.

Zn-a 2-glycoprotein, otherwise known as ZAG, occurs naturally in most body fluids, including blood, sweat, saliva, and urine. Researchers first isolated ZAG from blood samples more than 30 years ago, "but it’s been a molecule in search of a function for a long time," said Pamela Bjorkman, an HHMI investigator at the California Institute of Technology in Pasadena. Bjorkman, Luνs Sαnchez and HHMI associate Arthur Chirino published ZAG’s structure in the March 19, 1999, issue of the journal Science.

One of the mysteries surrounding ZAG is that it seems to be related to a large family of proteins known as class I major histocompatibility complex (MHC) molecules. These molecules bind to small pieces of other proteins, known as antigenic peptides, and in so doing trigger an immune response to invading microorganisms and viruses. Yet despite ZAG's similarity to MHC proteins, it apparently does not have a role in the immune system, Bjorkman said.

Last year, however, researchers at Aston University in Birmingham, U.K., discovered that ZAG is involved in cachexia, a wasting syndrome that can affect people with cancer, AIDS and other terminal illnesses. Cachexia can result in rapid, life-threatening weight loss and lead to shedding of both fat and muscle.

ZAG appears to drive the fat-loss in cancer patients. When the British investigators added ZAG to fat cells, the cells rapidly metabolized lipids, a major component of fat. Further evidence of ZAG's role in fat breakdown came when researchers, who fed the protein to genetically obese mice, noticed that he mice lost body fat even though they maintained normal eating habits. If ZAG produces the same effect in humans and is deemed safe, Bjorkman adds, it could provide a long-sought treatment for clinical obesity.

Understanding how ZAG boosts fat breakdown is a necessary precursor to any plans to develop ZAG-based obesity drugs. Knowing that structure often reveals details about function, Bjorkman's group created a molecular map of ZAG's structure using x-ray crystallography, which provides a three-dimensional picture revealing the location of each of the molecule's atoms. Surprisingly, this image showed that ZAG's structure is even more like that of its MHC relatives than researchers had previously thought.

One distinguishing feature of MHC proteins is a large groove that the molecules use to bind antigenic peptides. Bjorkman's group discovered that ZAG also has this groove, but unlike MHC molecules, ZAG's groove doesn't bind peptides. "We found that the ZAG groove contains some sort of compound. We know that it's not a peptide, but we haven't identified it yet," Bjorkman said. A search of small molecule databases for molecules capable of fitting in the groove failed to find any good candidates among known compounds.

Bjorkman's top priority is to find the molecule that binds in ZAG's groove, since this unknown partner may hold the key to understanding how ZAG promotes fat breakdown. "There's a big hint there," said Bjorkman, "we just don't know what the answer is yet. But once we identify this compound, it's possible you could inhibit the binding of this molecule to ZAG as a treatment for cachexia." She added that such a strategy might be particularly helpful for breast cancer patients since ZAG accumulates in 40 percent of cancerous breast tissue.

The information about ZAG's structure also provides important clues about the evolution of the MHC protein family. Bjorkman explained that prior to this and other structural work on MHC-related proteins, researchers believed that the MHC molecule groove evolved to bind antigenic peptides. Given the fact that ZAG shares this structure yet is not involved in the immune system suggests that the groove may have evolved for a different reason, she says.

"Perhaps the groove first evolved for a purpose other than antigen binding and MHC molecules have just capitalized on its existence," said Bjorkman. "But there's still a lot we don't understand." Determining ZAG's structure, she added, is simply the first step towards understanding how the molecule does its job.


Story Source:

The above story is based on materials provided by Howard Hughes Medical Institute. Note: Materials may be edited for content and length.


Cite This Page:

Howard Hughes Medical Institute. "Structure Of Fat-Depleting Protein Reveals Important Functional Clues." ScienceDaily. ScienceDaily, 19 March 1999. <www.sciencedaily.com/releases/1999/03/990319061346.htm>.
Howard Hughes Medical Institute. (1999, March 19). Structure Of Fat-Depleting Protein Reveals Important Functional Clues. ScienceDaily. Retrieved July 23, 2014 from www.sciencedaily.com/releases/1999/03/990319061346.htm
Howard Hughes Medical Institute. "Structure Of Fat-Depleting Protein Reveals Important Functional Clues." ScienceDaily. www.sciencedaily.com/releases/1999/03/990319061346.htm (accessed July 23, 2014).

Share This




More Health & Medicine News

Wednesday, July 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Courts Conflicted Over Healthcare Law

Courts Conflicted Over Healthcare Law

AP (July 22, 2014) — Two federal appeals courts issued conflicting rulings Tuesday on the legality of the federally-run healthcare exchange that operates in 36 states. (July 22) Video provided by AP
Powered by NewsLook.com
Why Do People Believe We Only Use 10 Percent Of Our Brains?

Why Do People Believe We Only Use 10 Percent Of Our Brains?

Newsy (July 22, 2014) — The new sci-fi thriller "Lucy" is making people question whether we really use all our brainpower. But, as scientists have insisted for years, we do. Video provided by Newsy
Powered by NewsLook.com
Scientists Find New Way To Make Human Platelets

Scientists Find New Way To Make Human Platelets

Newsy (July 22, 2014) — Boston scientists have discovered a new way to create fully functioning human platelets using a bioreactor and human stem cells. Video provided by Newsy
Powered by NewsLook.com
Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

TheStreet (July 21, 2014) — New research shows Gilead Science's drug Sovaldi helps in curing hepatitis C in those who suffer from HIV. In a medical study, the combination of Gilead's Hep C drug with anti-viral drug Ribavirin cured 76% of HIV-positive patients suffering from the most common hepatitis C strain. Hepatitis C and related complications have been a top cause of death in HIV-positive patients. Typical medication used to treat the disease, including interferon proteins, tended to react badly with HIV drugs. However, Sovaldi's %1,000-a-pill price tag could limit the number of patients able to access the treatment. TheStreet's Keris Lahiff reports from New York. Video provided by TheStreet
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins