Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Evolution provides clue to blood clotting

21.07.2011
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.

Dang LT, Purvis AR, Huang RH, Westfield LA, Sadler JE. Phylogenetic and functional analysis of histidine residues essential for pH-dependent multimerization of von Willebrand Factor. Journal of Biological Chemistry. July 2011.

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

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Julia Evangelou Strait | EurekAlert!
Further information:
http://www.wustl.edu

More articles from Life Sciences:

nachricht Fingerprint' technique spots frog populations at risk from pollution
27.03.2017 | Lancaster University

nachricht Parallel computation provides deeper insight into brain function
27.03.2017 | Okinawa Institute of Science and Technology (OIST) Graduate University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Northern oceans pumped CO2 into the atmosphere

27.03.2017 | Earth Sciences

Fingerprint' technique spots frog populations at risk from pollution

27.03.2017 | Life Sciences

Big data approach to predict protein structure

27.03.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>