Folding: Bad Proteins Branch Out
    By News Staff | December 4th 2013 05:00 AM | 1 comment | Print | E-mail | Track Comments

    A method to model the way proteins fold, and sometimes misfold, has revealed branching behavior that may have implications for Alzheimer's and other aggregation diseases. 

    In an earlier study of the muscle protein titin, Rice chemist Peter Wolynes and colleagues analyzed the likelihood of misfolding in proteins, in which domains – discrete sections of a protein with independent folding characteristics – become entangled with like sequences on nearby chains. They found the resulting molecular complexes called "dimers" were often unable to perform their functions and could become part of amyloid fibers.

    This time, Wolynes and his co-authors, Rice postdoctoral researcher Weihua Zheng and graduate student Nicholas Schafer, modeled constructs containing two, three or four identical titin domains. They discovered that rather than creating the linear connections others had studied in detail, these proteins aggregated by branching; the proteins created structures that cross-linked with neighboring proteins and formed gel-like networks that resemble those that imbue spider silk with its remarkable flexibility and strength.

    Two types of aggregate structures found in new work by researchers at Rice University are shown in three-dimensional (top) and simplified two-dimensional (bottom) representations. In the 2-D model, bold colors indicate the actual structures found in the AWSEM molecular dynamics simulations and the light colors are examples of how these structures might further develop in the presence of more protein copies. In each protein, there are two sticky segments, shown in orange and blue. A solid line represents the rest of each protein. Dashed lines represent stabilizing interactions formed between two sticky segments from different proteins. A fibrillar structure is shown on the left and a branching structure is shown on the right. The presence of two or more sticky segments in one protein allows for a greater diversity of possible aggregate structures. This realization should spur protein scientists to design experiments to investigate these different types of structures and their potential role in misfolding-related diseases. Credit: Weihua Zheng and Nick Schafer/Rice University

    "We're asking with this investigation, What happens after that first sticky contact forms?" Wolynes said. "What happens if we add more sticky molecules? Does it continue to build up further structure out of that first contact?

    "It turned out this protein we've been investigating has two amyloidogenic segments that allow for branch structures. That was a surprise," he said.

    The researchers used their AWSEM (Associative memory, Water-mediated Structure and Energy Model) program to analyze how computer models of muscle proteins interact with each other, particularly in various temperatures that determine when a protein is likely to fold or unfold.

    The program relies on Wolynes' groundbreaking principle of minimal frustration to determine how the energy associated with amino acids, bead-like elements in a monomer chain, determines their interactions with their neighbors as the chain folds into a useful protein.

    Proteins usually fold and unfold many times as they carry out their tasks, and each cycle is an opportunity for it to misfold. When that happens, the body generally destroys and discards the useless protein. But when that process fails, misfolded proteins can form the gummy amyloid plaques often found in the brains of Alzheimer's patients.

    The titin proteins the Rice team chose to study are not implicated in disease but have been well-characterized by experimentalists; this gives the researchers a solid basis for comparison.

    "In the real muscle protein, each domain is identical in structure but different in sequence to avoid this misfolding phenomenon," Wolynes said. So experimentalists studying two-domain constructs made the domains identical in every way to look for the misfolding behavior that was confirmed by Rice's earlier calculations. That prompted Wolynes and his team to create additional protein models with three and four identical domains.

    "The experiments yield coarse-grained information and don't directly reveal detail at the molecular level," Schafer said. "So we design simulations that allow us to propose candidate misfolded structures. This is an example of how molecular models can be useful for investigating the very early stages of aggregation that are hard to see in experiments, and might be the stages that are the most medically relevant."

    "We want to get the message across that this is a possible scenario for misfolding or aggregation cases -- that this branching does exist," Zheng added. "We want experimentalists to know this is something they should be looking for."

    Wolynes said the lab's next task is to model proteins that are associated with specific diseases to see what might be happening at the start of aggregation. "We have to investigate a wider variety of structures," he said. "We have no new evidence these branching structures are pathogenic, but they're clearly an example of something that happens that has been ignored until now.

    "I think this opens up new possibilities in what kind of structures we should be looking at," he said.

     Published in the Proceedings of the National Academy of Sciences.
    Source: Rice University


    Bonny Bonobo alias Brat

    This Australian Broadcasting Corporation (ABC) article on September 26th 2013 also claimed that recent findings about protein misfoldings bring scientists ‘a step closer to understanding motor neurone disease’. The interview revealed how it has been discovered that up to 90% of people in the World currently suffering from MND or ALS and who have died from MND or ALS in the past, have possibly developed the disease after exposure to neurodegenerative toxins that are in blue green algae which can bioaccumulate  in our food and water supply and ultimately in us :-

     "We think [the cause is] a toxin that's found in blue green algae and can get into all kinds of food stuffs, into fish, into crustaceans, into seeds of trees," Dr Dunlop said.
    "It can move through the food chain and bio-concentrate and when people are exposed to it, it seems to be able to trigger motor neurone disease in some people.
    "It's fascinating. The algal toxin actually mimics an amino acid that humans use to make their own proteins, and if its in your body at the time, it can trick yourselves into thinking it's the one that you normally use.”
    "Then when it gets into your proteins it can prevent them from folding and functioning properly, and that can lead to toxicity."

    Here is a TED  talk given by Dr Paul Alan Cox explaining how blue green algae and toxic BMAA can potentially be causing up to 90% of ALS and has been directly linked to Alzheimer's and Parkinson's diseases and how an L-Serine treatment is currently being tested to treat ALS and other neurodegenerative diseases by hopefully reversing or preventing the misfolding of the proteins caused by BMAA. 

    The PLOSONE article is called 'The Non-Protein Amino Acid BMAA Is Misincorporated into Human Proteins in Place of l-Serine Causing Protein Misfolding and Aggregation' and it was produced by Rachael Anne Dunlop, Paul Alan Cox, Sandra Anne Banack& Kenneth John Rodgers.
    My latest forum article 'Australian Researchers Discover Potential Blue Green Algae Cause & Treatment of Motor Neuron Disease (MND)&(ALS)' Parkinsons's and Alzheimer's can be found at