Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Modifying Proteins to Combat Disease

Published: Monday, January 28, 2013
Last Updated: Monday, January 28, 2013
Bookmark and Share
The results of this research can be utilized to provide new direction and focus in the race to create drugs to combat disease, especially cancer.

Transmitting from one generation to the next the genetic message encoded in DNA is a well-understood concept in biology. There is now increasing awareness that chemical modifications of DNA and associated proteins are also transmitted across generations, and these changes are critical in determining the way the genetic message is read. Detailed understanding of the structures of the proteins that effect these changes is therefore highly coveted information. Thanks to the efforts of a research team from Eli Lilly and Company, with the help of the Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beamline 31-ID at the U.S. Department of Energy Office of Science’s Advanced Photon Source, the structure of an important methylation enzyme is now known.

A prime example of chemical modifications is the addition of a methyl group (methylation) to the side-chain of arginine residues of proteins, dramatically altering their activity and interactions. Aberrant methylation has been linked to a wide variety of diseases, most notably cancer.

The Lilly research team investigated a protein from a group of enzymes known as protein arginine methyltransferases (PRMTs), which play important roles in cell signaling, gene regulation, and the transport of proteins and nucleic acids.

The team focused on PRMT5, which had been previously shown to be part of a complex of partner proteins that help regulate its function and specificity. Because enhanced levels of PRMT5 have been observed in various types of cancer, it is a focus of anti-cancer drug research.

In particular, the researchers were interested in how PRMT5 interacts with methylosome protein 50 (MEP50), known to be a critical mediator of binding with other members of the protein complex and with substrates. Phosphorylation of either MEP50 or of PRMT5 itself can control methyltransferase activity of PRMT5. Activation of the methyltransferase activity of PRMT5 was known to prolong survival of tumor cells while mutants that disrupt its association with MEP50 inhibited that methyltransferase activity.

Since MEP50 activity has been linked especially to ovarian and prostate cancer, details of its structure and modes of interaction with PRMT5 and other members of the binding complex are prime targets of current research.

The research team determined a definitive structure for PRMT5 in interaction with MEP50, bound to a peptide derived from histone H4. The team combined data from chromatography, sedimentation analysis, enzymology, and x-ray crystallography using data collected at 31-ID to elucidate the structure and activity of the PRMT5:MEP50 complex.

The resulting structure yielded a surprise: a hetero-octameric complex that shows close interaction between a seven-bladed propeller-like MEP50 and the N-terminal domain of PRMT5. The structure offers a clear view of how substrate recognition occurs and points the way toward promising targets for drug design.

The researchers were able to compare their data from human PRMT5 with newly published data on PRMT5 from the nematode worm, which shows 31% sequence identity with human PRMT5. The dimeric PRMT5 complex in the nematode was strikingly different than the large octameric human PRMT5, in which four molecules of PRMT5 and four of MEP50 form the functional core of the PRMT5 complexes.

This important octameric structural core in human PRMT5 is proposed as the main driver of interactions with partner proteins to create a multimeric complex of subunits with different specificities and functions. In addition, when compared with what was previously known about PRMTs, important differences in the three-dimensional structure of PRMT5 and how it interacts with MEP50 were discovered.

Such critical details will be all-important in anti-cancer drug design. The structural data also allow the role of MEP50 to be expanded by suggesting its importance in recruiting substrates and partners to PRMT5.

By providing a detailed structure of PRMT5 in interaction with MEP50, the research team has revealed critical insights about posttranslational methylation and identified promising target sites for drugs to combat cancer and other diseases related to methylation processes.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,900+ scientific posters on ePosters
  • More Than 4,200+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

New Commercial Method for Producing Medical Isotope
The effort to secure a stable, domestic source of a critical medical isotope reached an important milestone this month as scientists demonstrated the production, separation and purification of molybdenum-99 (Mo-99.
Wednesday, June 17, 2015
Self-Assembly of Layered Membranes
Scientists used self-assembly under controlled conditions to create a membrane consisting of layers with distinctly different structures.
Monday, October 27, 2014
Argonne National Laboratory Develops Open-source Analysis Tool for Annotation of Metagenomes
The new metagenomic RAST server is designed specifically for use with data generated by 454 Sequencing™ systems.
Monday, November 24, 2008
Argonne's Joachimiak and Rosenbaum Honored with 2007 Compton Award
The 2007 Compton Award was presented for pioneering advances and leadership that helped to establish the APS as a premier location worldwide for protein crystallography research.
Wednesday, May 16, 2007
Argonne Contribute 1,000th Structure to Protein Data Bank
The 1,000th deposit provides insight into how cells sense and communicate information.
Wednesday, February 01, 2006
Scientific News
Food Triggers Creation of Regulatory T Cells
IBS researchers document how normal diet establishes immune tolerance conditions in the small intestine.
Light Signals from Living Cells
Fluorescent protein markers delivered under high pressure.
Counting Cancer-busting Oxygen Molecules
Researchers from the Centre for Nanoscale BioPhotonics (CNBP), an Australian Research Centre of Excellence, have shown that nanoparticles used in combination with X-rays, are a viable method for killing cancer cells deep within the living body.
Therapeutic Approach Gives Hope for Multiple Myeloma
A new therapeutic approach tested by a team from Maisonneuve-Rosemont Hospital (CIUSSS-EST, Montreal) and the University of Montreal gives promising results for the treatment of multiple myeloma, a cancer of the bone marrow currently considered incurable with conventional chemotherapy and for which the average life expectancy is about 6 or 7 years.
Cellular 'Relief Valve'
A team led by scientists at The Scripps Research Institute (TSRI) has solved a long-standing mystery in cell biology by showing essentially how a key “relief-valve” in cells does its job.
Genomic Signature Shared by Five Types of Cancer
National Institutes of Health researchers have identified a striking signature in tumor DNA that occurs in five different types of cancer.
Protein Protects Against Flu in Mice
The engineered molecule doesn’t provoke inflammation and may hail a new class of antivirals.
Cat Stem Cell Therapy Gives Humans Hope
By the time Bob the cat came to the UC Davis veterinary hospital, he had used up most of his nine lives.
Crowdfunding the Fight Against Cancer
From budding social causes to groundbreaking businesses to the next big band, crowdfunding has helped connect countless worthy projects with like-minded people willing to support their efforts, even in small ways. But could crowdfunding help fight cancer?
Switch Lets Salmonella Fight, Evade Immune System
Researchers at the University of Illinois at Chicago have discovered a molecular regulator that allows salmonella bacteria to switch from actively causing disease to lurking in a chronic but asymptomatic state called a biofilm.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,900+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,200+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!