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 Organ-on-a-chip mimics heart's biomechanical properties
23.02.2017 | Vanderbilt University

nachricht Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München

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: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>