Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cancer risk takes shape

16.10.2001


About half of all patients with hereditary breast or ovarian cancer have mutations in a gene called BRCA1. Now the first images of the protein the gene encodes, BRCA1, are helping researchers work out how the mutations cause human disease.





The pictures reveal fine detail of how BRCA1 interacts with other proteins. Such information should help researchers work out how BRCA1 prevents cells becoming cancerous. They suspect that it is involved in DNA repair, controlling cell division and regulating gene activity.

Understanding BRCA1 should also make it easier to design genetic screening programmes to identify individuals at risk and catch cancer early. This is "very important to long-term survival," says Mark Glover of the University of Alberta in Edmonton, Canada, leader of one of the teams that have solved parts of BRCA1’s structure.


BRCA1 is a big protein — three times the size of haemoglobin, for example. Its chain of 1,863 amino acid links folds into a complex three-dimensional structure. Like a molecular Swiss Army knife, different parts are designed for different jobs.

Most of the mutations associated with breast and ovarian cancers beset the two regions composed of amino acids at the chain ends now under scrutiny. These areas vary least between different species, showing that their function is important enough for natural selection to stamp out slip-ups that would lead to variation.

The ends are probably the most important parts of the molecule, says Richard Baer, a cancer researcher at Columbia University in New York. "They won’t be the whole story, but they’re a big part of the story," he says.

Marked for death

One end of BRCA1 — the ’N’ terminus — bonds to another protein. The two form a catalyst that joins a small molecule called ubiquitin to other proteins. Ubiquitin tags proteins for destruction — an important stage in the body’s defence against cancer.

This much was already known. Rachel Klevit, of the University of Washington in Seattle, and colleagues have now visualized the interface between BRCA1 and its catalytic collaborator using nuclear magnetic resonance spectroscopy.

Klevit’s team was surprised to find that the collaborator joins to a different part of BRCA1 than they had suspected. The structure shows that mutations can disrupt either this junction or the ubiquitin-attachment machinery.

A full understanding of the N-terminal region’s workings might allow mutant BRCA1 proteins to be repaired, using small molecules to enhance or disrupt the protein machine, says Klevit. Unfortunately the many proteins that interact with BRCA1 make this a daunting task.

"We can do these sorts of things on the chalkboard, but until we’re clear on the multiple functions of all these different proteins it’s going to be difficult," says Klevit.

Pack up

Glover’s group focused on the other end of the molecule, the ’C’ terminus. Here, around 100 amino acids form structures known as BRCT repeats. These often feature in proteins that repair DNA — a vital part of tumour suppression.

X-ray crystallography reveals that the two BRCT repeats in BRCA1 "pack in a very intimate manner", says Glover. Mutations that alter the repeats disrupt their packing and unravel the protein. The loss of the last 11 amino acids at the protein’s C terminus is associated with aggressive, early-onset breast cancer.

The structures Klevit’s and Glover’s groups reveal are common to a range of proteins, but between them lies a large stretch of terra incognita, "that doesn’t look like any other protein", says Klevit. These amino acids — more than 1,500 of them — must do something, she says: "Nature’s not wasteful of its resources."


letters
Structure of a BRCA1–BARD1 heterodimeric RING–RING complex

PETER S. BRZOVIC, PONNI RAJAGOPAL, DAVID W. HOYT, MARY-CLAIRE KING & RACHEL E. KLEVIT
Nature Structural Biology 8, 833-837 (October 2001)

letters
Crystal structure of the BRCT repeat region from the breast cancer-associated protein BRCA1

R. SCOTT WILLIAMS, RUTH GREEN & J.N. MARK GLOVER
Nature Structural Biology 8, 838-842 (October 2001)


JOHN WHITFIELD | Nature News Service
Further information:
http://www.nature.com/cancer/hotp/200110/4.html
http://www.nature.com/cancer/

More articles from Health and Medicine:

nachricht How cancer metastasis happens: Researchers reveal a key mechanism
19.01.2018 | Weill Cornell Medicine

nachricht Researchers identify new way to unmask melanoma cells to the immune system
17.01.2018 | Duke University Medical Center

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Let the good tubes roll

19.01.2018 | Materials Sciences

How cancer metastasis happens: Researchers reveal a key mechanism

19.01.2018 | Health and Medicine

Meteoritic stardust unlocks timing of supernova dust formation

19.01.2018 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>