Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

So many proteins, so much promise

31.10.2011
New top-down strategy of identifying proteins could lead to early detection of disease

The human genome has been mapped. Now, it's on to proteins, a much more daunting task. There are 20,300 genes, but there are millions of distinct protein molecules in our bodies. Many of these hold keys to understanding disease and targeting treatment.

A team led by Northwestern University chemical biologist Neil Kelleher has developed a new "top-down" method that can separate and identify thousands of protein molecules quickly. Many have been skeptical that such an approach, where each protein is analyzed intact instead of in smaller parts, could be done on such a large scale.

The promise of a top-down strategy is that the molecular data scientists do collect will be more closely linked to disease.

"Accurate identification of proteins could lead to the identification of biomarkers and early detection of disease as well as the ability to track the outcome of treatment," Kelleher said. "We are dramatically changing the strategy for understanding protein molecules at the most basic level. This is necessary for the Human Proteome Project -- the mapping of all healthy human proteins in tissues and organs -- to really take off."

Kelleher is the Walter and Mary E. Glass Professor of Molecular Biosciences and professor of chemistry in the Weinberg College of Arts and Sciences. He also is director of the Proteomics Center of Excellence and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Kelleher says his approach is conceptually simple. "We take proteins -- those swimming around in cells -- and we measure them," he said. "We weigh proteins precisely and identify them directly. The way everyone else is doing it is by digesting the proteins, cutting them up into smaller bits called peptides, and putting them back together again. I call it the Humpty Dumpty problem."

The new strategy, Kelleher says, solves the "protein isoform problem" of the "bottom-up" approach where the smaller peptides often do not map cleanly to single human genes. The study will be published Oct. 30 by the journal Nature.

The top-down method can accurately identify which gene produced which protein. The bottom-up method is only 60 to 90 percent accurate in identifying proteins precisely.

"We need to define all the protein molecules in the human body," Kelleher said. "First, we need a map of healthy protein forms, which will become a highly valuable reference list for understanding damaged and diseased forms of proteins. Our technology should allow us to get farther down this road faster."

In the first large-scale demonstration of the top-down method, the researchers were able to identify more than 3,000 protein forms created from 1,043 genes from human HeLa cells.

Their goal was to identify which gene each protein comes from -- to provide a one-to-one picture. They were able to produce this accurate map of thousands of proteins in just a few months.

The researchers also can produce the complete atomic composition for each protein. "If a proton is missing, we know about it," Kelleher said.

One gene they studied, the HMGA1 gene associated with premature aging of cells, produces about 20 different protein forms.

Kelleher's team developed a four-dimensional separation system that uses separations and mass spectrometry to measure the charge, mass and weight of each protein as well as how "greasy" a protein is. The software the researchers developed to analyze the data during years of work prior to the study proved critical to the success of the top-down method.

"If you want to know how the proteins in cancer really work and change, top-down mass spectrometry is getting to the point where it can be part of the discussion," Kelleher said.

"Analyzing the entire set of proteins expressed in a cell presents a continuing and significant technical challenge to the field of proteomics," said Charles Edmonds, who oversees proteomics grants at the National Institute of General Medical Sciences of the National Institutes of Health. "By combining multiple fractionation technologies with mass spectrometry, Dr. Kelleher and colleagues have demonstrated more than an order of magnitude improvement in proteome coverage. This is a great start."

The title of the paper is "Mapping Intact Protein Isoforms in Discovery Mode Using Top-Down Proteomics." In addition to Kelleher, 17 other co-authors contributed to the study.

Megan Fellman | EurekAlert!
Further information:
http://www.northwestern.edu

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton 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: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Water - as the underlying driver of the Earth’s carbon cycle

17.01.2017 | Earth Sciences

Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

17.01.2017 | Materials Sciences

Smart homes will “LISTEN” to your voice

17.01.2017 | Architecture and Construction

VideoLinks
B2B-VideoLinks
More VideoLinks >>>