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Seattle Researchers Uncover Structure Of Blood-Clotting Protein Involved In Most Common Form Of Hemophilia

Date:
November 30, 1999
Source:
Fred Hutchinson Cancer Research Center
Summary:
For the first time, researchers have described the structure of a key blood-clotting protein implicated in hemophilia A, the most prevalent and serious type of hemophilia, an inherited disorder that causes recurrent, uncontrolled bleeding, most often into the joints.
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Discovery provides key for development of improved blood-clotting drugs for hemophiliacs and better blood-thinning medications for those at risk of stroke and heart attack

SEATTLE - For the first time, researchers have described the structure of a key blood-clotting protein implicated in hemophilia A, the most prevalent and serious type of hemophilia, an inherited disorder that causes recurrent, uncontrolled bleeding, most often into the joints.

Knowing the structure of this protein, called factor VIII, gives scientists a first-hand glimpse at the subtle changes - often involving just a single errant atom - that cause this devastating bleeding disorder, which affects about one in 10,000 American males. This discovery also provides a key to the development of new drugs - better clotting agents for hemophiliacs and improved anticoagulants for those at risk of stroke and heart attack.

The discovery, a collaborative effort between researchers at the Fred Hutchinson Cancer Research Center and the University of Washington, will be reported tomorrow (Thursday, Nov. 25) in the British journal Nature. The Hutchinson Center team was led by senior author Barry L. Stoddard, Ph.D., and included Kate Pratt, Ph.D., and Betty Shen, Ph.D., all of the Center's Basic Sciences Division. The UW group was led by Earl W. Davie, Ph.D., and Kazuo Fujikawa, Ph.D., both of the Biochemistry Department within the School of Medicine.

"Solving the structure of this protein tells us a great deal about how it works. It also explains very specifically, at the atomic level, why factor VIII doesn't work in many people with hemophilia A," says Stoddard, a member of the Hutchinson Center's Basic Sciences Division and an affiliate associate professor of biochemistry at UW.

Using a technique called X-ray crystallography - an ultra-high-powered form of microscopy that reveals the structure of matter at the atomic level - the researchers uncovered the architecture of a region within factor VIII called the C2 domain. This particular region of the protein harbors many functional genetic mutations - and corresponding structural defects - responsible for hemophilia A.

"A huge percentage of the total function of the factor VIII protein is tied up in this little domain at the end of the protein chain," Stoddard says, referring to the string of some 2,300 amino acids that comprises the huge factor VIII protein. Along this chain are sections of amino acids folded into six independent regions, or domains, each with a highly specific function. The job of the C2 domain is to seek out any injury to the circulatory system and immediately help trigger a clotting response in that precise location. The researchers are particularly excited about the potential medical applications of their discovery.

"Now that we understand the structure of this critical regulatory protein, which is absolutely specific to blood clotting, we can hopefully exploit it as a target for developing anti-clotting agents," Stoddard says. Unique compounds could be identified as candidates for drug development against stroke, heart attack and thrombosis within the next three years, he predicts.

Currently, the only available blood thinners are "non-specific" - they can produce a wide range of side effects because they act on a vast number of proteins and enzymes throughout the body, not just those that regulate blood clotting. Knowing the structure of the factor VIII protein could allow researchers to develop drugs that act much more selectively and thus produce few or no side effects.

Unlocking the structure of factor VIII also could lead to the development of improved therapies to treat hemophilia A. The current standard of treatment for hem


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Materials provided by Fred Hutchinson Cancer Research Center. Note: Content may be edited for style and length.


Cite This Page:

Fred Hutchinson Cancer Research Center. "Seattle Researchers Uncover Structure Of Blood-Clotting Protein Involved In Most Common Form Of Hemophilia." ScienceDaily. ScienceDaily, 30 November 1999. <www.sciencedaily.com/releases/1999/11/991130064333.htm>.
Fred Hutchinson Cancer Research Center. (1999, November 30). Seattle Researchers Uncover Structure Of Blood-Clotting Protein Involved In Most Common Form Of Hemophilia. ScienceDaily. Retrieved March 18, 2024 from www.sciencedaily.com/releases/1999/11/991130064333.htm
Fred Hutchinson Cancer Research Center. "Seattle Researchers Uncover Structure Of Blood-Clotting Protein Involved In Most Common Form Of Hemophilia." ScienceDaily. www.sciencedaily.com/releases/1999/11/991130064333.htm (accessed March 18, 2024).

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