Alzheimer's, Parkinson's and type II diabetes: New way to target shape-shifting proteins
ScienceDaily (Aug. 28, 2011) ? A molecule which can stop the formation of long protein strands, known as amyloid fibrils, that cause joint pain in kidney dialysis patients has been identified by researchers at the University of Leeds. The discovery could lead to new methods to identify drugs to prevent, treat or halt the progression of other conditions in which amyloid fibrils play a part, including Alzheimer's, Parkinson's and type II diabetes.
The research, funded by the Biotechnology and Biological Sciences Research Council and the Wellcome Trust, is published August 28 in Nature Chemical Biology.
The team -- from Leeds' Astbury Centre for Structural Molecular Biology and Faculty of Biological Sciences -- found that an antibiotic known as Rifamycin SV was able to prevent the protein ?2microglobulin (?2m) from forming into fibrils. ?2m is known to accumulate in renal dialysis patients and forms fibrils within the joints, causing extreme pain and arthritis.
By using a specialised analytical technique called ion mobility spectrometry-mass spectrometry (IMS-MS), the researchers were able to see at what stage of the process Rifamycin SV prevented amyloid fibril formation. They believe the technique could enable potential drugs to be identified for the many other proteins which form amyloid fibrils, linked to a wide range of human disorders.
"Traditional drug design for diseases like Alzheimer's is incredibly difficult because the proteins you're trying to target are changing shape and structure all the time," explains University of Leeds Professor of Structural Molecular Biology, Sheena Radford. "It's like trying to consistently pick out one bead of a particular shape from box of potentially millions of similar beads. This new technique allows us to see the shape of the protein as it changes, so we can more easily identify exactly which part we need to target."
In their normal, folded state, proteins are unable to link together to form long fibrillar assemblies, but if they unfold, they expose areas where they can bind to each other. Initially they form small groups of two, three or four proteins, and then these link into long strands, which twist together to form fibrils.
Most analytical techniques can only show the mass of the protein or its make-up in terms of amino acids, neither of which changes as the protein unfolds. Others are unable to look at individual molecules within complex mixtures. However, IMS-MS can measure the mass and shape of a protein, allowing researchers to watch the unfolding process and the aggregation into small groups and then assembly into the fibril and to find which of these species is able to bind a ligand and stop the assembly process.
In the research published August 28, researchers found that Rifamycin SV stopped the formation of protein fibrils by binding to an unfolded protein molecule with a particular shape, enabling for the first time, an unfolded protein of a particular shape to be identified as a target for the design of new inhibitors of fibril assembly.
"We're fortunate to be one of the few universities in the UK able to use IMS-MS to study amyloid fibril formation," says Professor of Biomolecular Mass Spectrometry, Alison Ashcroft, who specialises in this type of analysis. "Although fibrils take years to develop in the body, we are able to 'grow' them in hours in the lab. By using IMS-MS to help us map exactly how they are formed, we can better understand the mechanism by which it happens and -- we hope -- find ways to stop it."
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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Leeds, via EurekAlert!, a service of AAAS.
Journal Reference:
- Lucy A Woods, Geoffrey W Platt, Andrew L Hellewell, Eric W Hewitt, Steve W Homans, Alison E Ashcroft, Sheena E Radford. Ligand binding to distinct states diverts aggregation of an amyloid-forming protein. Nature Chemical Biology, 2011; DOI: 10.1038/nchembio.635
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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.
Source: http://feeds.sciencedaily.com/~r/sciencedaily/~3/wGNYXaTpy7Y/110828140938.htm
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A reader of Dear Annabelle asked me about having a threesome with her husband and it got me to thinking? ?An astounding amount of married couples cheat on one another. ?As I got older and began having more friends who were married, I was actually shocked at the rampant amount of infidelity I was witnessing. ?I even have a reader question about this very subject (coming soon
In case you?re not familiar with the term, an open relationship means that the couple has physical intimacy outside of the marriage. ? I use the term ?physical intimacy? because not all couples agree to have sex outside of the marriage. ?Some couples agree to flirting or making out while others allow only oral pleasure. ?Couples in an open marriage make their own rules and the one common rule among most open relationships is that they do not become emotionally involved with anyone outside of the marriage.
Monogamy is a hard pill to swallow. ?Having sex with the same person for the rest of your life might seem suffocating and boring. ?Some couples are high school or college sweethearts and never had the opportunity to sow their oats. ?There are couples who are married to their first.
A lot. ?Cheating is done in secret and by cheating you are breaking the trust of your marriage. ?An open relationship is not cheating. ?You are having sex with another person with the permission of your partner. ?When you are having sex with another person, your partner will be aware of what you are doing unlike cheating when they just suspect.
Maybe. ?Sex is a crucial part of your relationship. ?It enforces your connection to one another and is a pretty awesome stress reliever. ?If your relationship has become stagnant and one of you have considered straying, maybe it?s something to consider. ?Maybe just talking about it will be enough to turn your on and rip each other?s clothes off. ?Maybe not.