Computer modeling used to study protein involved with cancer, aging and chronic disease

A new biophysical and biochemical study may lead to better understanding of how structural flexibility controls the interaction of a protein that is closely involved with cancer, aging and other chronic diseases -- thereby facilitating future development of better therapeutic strategies, according to a Kansas State University biochemist.

Jianhan Chen, an assistant professor of biochemistry, was one of the researchers on a collaborative project that took a combined computational and experimental approach to understand how protein p21 functions as a versatile regulator of cell division. Their latest findings, "Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21," were published in a recent edition of Nature Chemical Biology.

The study used computer simulation to rationalize results from biochemical and biophysical experiments, and provided further insights that would guide future investigations, Chen said. In this case, the focus is human protein p21 and its ability to function as an inhibitor of normal cell growth.

The protein has been shown to be an intrinsically disordered protein. This means it lacks a well-defined three-dimensional structure, characteristics that, until roughly a decade ago, were thought to be necessary for the protein to function.

"For a long time it was believed that proteins must fold to function and it was hard to imagine how an unfolded protein could play a role in crucial cellular areas," Chen said. "What researchers before me found was that by lacking a stable structure, this actually turned out to be really, really important to how these proteins function."

Along with being an intrinsically disordered protein, p21 is a versatile cyclin-dependent kinase, or Cdk, inhibitor -- meaning it adapts to and inhibits a range of Cdk-cyclin complexes that regulate eukaryote cell division. It also has been connected to cancer and aging. For example, Chen said p21 is a principal trans-activation target of the p53 tumor suppressor protein and contributes to p53-dependent tumor suppression.

"This protein is extremely challenging to study. It's highly dynamic and it's heterogeneous," Chen said. Because of this, mechanistic studies of intrinsically disordered proteins like p21 have been limited. Experiment alone is not sufficient and computer modeling is necessary to provide important missing details, he said. A tight integration of both could lead to a precise understanding of how structural flexibility influences function of p21 and other intrinsically disordered proteins.

"For me this is one of the most interesting IDPs," Chen said. "I'm a theorist and I want to use this system to understand the principles of how this type of proteins can perform their functions. Even though they are disordered, they are not random; there is no chaos. They still have some type of residual structures and certain features which allow function to be controlled in a precise way, and I want to understand the underlying mechanism of how this occurs."

Chen is continuing work with p21 and other small proteins that regulate cell cycles.

Provided by Kansas State University (news : web)

Cell component involved in triggering cat allergy

A breakthrough by scientists at The University of Nottingham could provide hope for any allergy sufferers who have ever had to choose between their health and their household pet.

The team of immunologists led by Drs Ghaem-Maghami and Martinez-Pomares in the University’s School of Molecular Medical Sciences, and funded by the charity Asthma UK, have identified a cell component which plays a key role in triggering allergic responses to cat dander.

The discovery furthers our understanding of how the body’s immune system identifies and reacts to allergens, which could pave the way in developing new ways of treating allergies.

The development is especially good news for the millions of people with asthma whose condition is often worsened by their allergy to airborne allergens from cat dander or house dust mite. Cat dander consists of microscopic pieces of cat skin which easily become airborne.

Dr. Amir Ghaem-Maghami said: “There has been a sharp increase in the prevalence of allergies over the past few decades and allergic asthma among children has reached epidemic proportions in many industrialised countries, including the UK.

“Despite improvements in patient care, three people die every day in the UK from asthma, and most therapies target symptoms rather than curing the condition.

“Many people with asthma are highly sensitive to airborne allergens such as cat dander or house dust mite — in fact many studies have shown that up to 40 per cent of children with asthma are allergic to cat allergens.

“A better understanding of how the interaction between allergens and the immune system leads to allergy is vital if we are to develop more effective and efficient treatments for this debilitating condition.”

Dr. Elaine Vickers, Research Relations Manager at Asthma UK, says: “We are delighted to see the rapid progress that Dr. Ghaem-Maghami and his colleagues are making in such a complex area of research.

“This is a great example of where Asthma UK’s research funding is leading to a better understanding of asthma which could ultimately benefit thousands of people with both asthma and allergies.”

Allergy is a disorder caused by the body’s immune system reacting to usually harmless substances found in the environment, known as allergens. Believing itself under attack, the immune system produces a molecule called IgE, which eventually leads to release of further chemicals (including histamine) by certain immune cells which together cause an inflammatory response and the classic symptoms of allergy — itchy eyes, sneezing, runny nose and wheezing.

The Nottingham work, recently published in the Journal of Biological Chemistry, has focused on the role of the mannose receptor (MR), a receptor found on the surface of dendritic cells. These cells are among the first cells in the immune system that come into contact with allergens.

The team recently found that the MR binds to a wide range of allergens and plays an important role in the allergic response to house dust mite allergens. In their latest study they looked at the contribution of MR to allergy caused by a major cat allergen called Fel d 1.

They were able to prove that MR is needed for the body to recognise Fel d 1 as a potential foreign invader and for the production of IgE against Fel d 1. The discovery shows that MR plays a pivotal role not only in recognising allergens but also in provoking the body’s allergic response to them.

Provided by University of Nottingham (news : web)