Featured Research

from universities, journals, and other organizations

Evolution provides clue to blood clotting

Date:
July 21, 2011
Source:
Washington University School of Medicine
Summary:
A simple cut to the skin unleashes a complex cascade of chemistry to stem the flow of blood. Now, scientists at have used evolutionary clues to reveal how a key clotting protein self-assembles. The finding sheds new light on common bleeding disorders.

The building blocks of von Willebrand Factor remain separate at the slightly basic pH of 7.4 (left). In a more acidic environment (right), the VWF building blocks self-assemble into long chains and form the protein’s signature helical tubules. This shape is vital to blood clotting. When VWF in the blood finds sites of injury, its helical tube unfurls to catch platelets and form blood clots.
Credit: J. Evan Sadler, MD, PhD

A simple cut to the skin unleashes a complex cascade of chemistry to stem the flow of blood. Now, scientists at Washington University School of Medicine in St. Louis have used evolutionary clues to reveal how a key clotting protein assembles. The finding sheds new light on common bleeding disorders.

The long tube-shaped protein with a vital role in blood clotting is called von Willebrand Factor (VWF). Made in cells that form the inner lining of blood vessels, VWF circulates in the blood seeking out sites of injury. When it finds them, its helical tube unfurls to catch platelets and form blood clots. Defects in VWF cause von Willebrand Disease, the most common inherited bleeding disorder in humans.

"The challenge for the cell is how to build this massive protein without clogging the machinery," says J. Evan Sadler, MD, PhD, professor of medicine and senior author of the study published in July in the Journal of Biological Chemistry. "The cell has solved this problem by making the assembly of von Willebrand Factor dependent on its location in the cell."

And VWF knows its location in a cell because pH, a measure of how acidic or basic a liquid is, varies from one cellular structure to the next. On a scale of 0 to 14, pure water has a neutral pH of about 7; human blood is slightly basic with a pH of 7.4.

In a cell, the building blocks of VWF form in an area with the same pH as blood. Then these building blocks are shipped to an area that is more acidic. Called the Golgi, this cellular compartment is known for its role in packaging proteins and has a pH of about 6.2. In this acidic environment, the building blocks of VWF are able to form long chains and fold into its signature helical tubules. But how this assembly process works has not been well understood.

From basic biophysics, Sadler and his colleagues knew that only one amino acid in the long protein chain is likely to "sense" a pH change from 7.4 to 6.2. Moving to an acidic environment, this amino acid, histidine, gains a positive charge. The group suspected that this charge may trigger the VWF building blocks to link together in a long chain.

But there are many histidines located throughout the chain. Like 26 letters of the alphabet form thousands of words, 20 essential amino acids form all proteins in the body. To identify which histidines might be guiding the amino acid chain to form the long VWF tubules, Sadler and his team looked to evolution.

"If a particular histidine is important in this process, it should be present in the same location across many species," Sadler says.

So Sadler's group, including the paper's first author, Luke T. Dang, who was an undergraduate student when he did this work, gathered the DNA sequences of VWF for humans, 19 other placental mammals, a marsupial, two birds, a reptile, an amphibian and five fish. Dang is now a graduate student at the University of Washington, Seattle.

"By lining up the sequences, we found a relatively small number of histidines that are in the same place across species," Sadler says. "It then becomes manageable to mutate them individually and see if that prevents von Willebrand Factor from assembling."

Out of the many histidines in the amino acid sequence of VWF, they found two that are important in sensing the pH change and guiding the building blocks to form chains in an acidic environment. When Dang replaced either of these histidines with an amino acid that provides no positive charge, the chain did not form. But when Dang forced a positive charge to always be present at these locations, the chain formed again.

"A positive charge at these positions is important for von Willebrand Factor to assemble properly so it can perform its biological function," says Sadler, also a hematologist who specializes in treating patients with blood clotting disorders. "Without VWF, you bleed."

According to Sadler, defects in VWF disproportionately affect women because the protein is especially important for controlling bleeding during menstruation and childbirth. Sadler says this work helps to better understand the defects in pathways that cause von Willebrand Disease and related conditions.

This work was supported by the National Institutes of Health (NIH) and the American Heart Association Midwest Affiliate Postdoctoral Fellowship Award.


Story Source:

The above story is based on materials provided by Washington University School of Medicine. The original article was written by Julia Evangelou Strait. Note: Materials may be edited for content and length.


Journal Reference:

  1. L. T. Dang, A. R. Purvis, R.-H. Huang, L. A. Westfield, J. E. Sadler. Phylogenetic and Functional Analysis of Histidine Residues Essential for pH-dependent Multimerization of von Willebrand Factor. Journal of Biological Chemistry, 2011; 286 (29): 25763 DOI: 10.1074/jbc.M111.249151

Cite This Page:

Washington University School of Medicine. "Evolution provides clue to blood clotting." ScienceDaily. ScienceDaily, 21 July 2011. <www.sciencedaily.com/releases/2011/07/110720151545.htm>.
Washington University School of Medicine. (2011, July 21). Evolution provides clue to blood clotting. ScienceDaily. Retrieved October 1, 2014 from www.sciencedaily.com/releases/2011/07/110720151545.htm
Washington University School of Medicine. "Evolution provides clue to blood clotting." ScienceDaily. www.sciencedaily.com/releases/2011/07/110720151545.htm (accessed October 1, 2014).

Share This



More Plants & Animals News

Wednesday, October 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Attacking Superbugs

Attacking Superbugs

Ivanhoe (Oct. 1, 2014) — Two weapons hospitals can use to attack superbugs. Scientists in Ireland created a new gel resistant to superbugs, and a robot that can disinfect a room in minutes. Video provided by Ivanhoe
Powered by NewsLook.com
Cultural Learning In Wild Chimps Observed For The First Time

Cultural Learning In Wild Chimps Observed For The First Time

Newsy (Oct. 1, 2014) — Cultural transmission — the passing of knowledge from one animal to another — has been caught on camera with chimps teaching other chimps. Video provided by Newsy
Powered by NewsLook.com
Earth Has Lost Half Its Vertebrate Wildlife Since 1970: WWF

Earth Has Lost Half Its Vertebrate Wildlife Since 1970: WWF

Newsy (Sep. 30, 2014) — A new study published by the World Wide Fund for Nature found that more than half of the world's wildlife population has declined since 1970. Video provided by Newsy
Powered by NewsLook.com
Annual Dog Surfing Competition Draws California Crowds

Annual Dog Surfing Competition Draws California Crowds

AFP (Sep. 30, 2014) — The best canine surfers gathered for Huntington Beach's annual dog surfing competition, "Surf City, Surf Dog." Duration: 01:15 Video provided by AFP
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:

Strange & Offbeat Stories

 

Plants & Animals

Earth & Climate

Fossils & Ruins

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