The amino acid selenocysteine may be the key to curing diseases that result from misfolding of proteins
Proteins are the building blocks of body cells. They are responsible for activities such as dividing the cells in the body, maintaining them (cleaning waste and producing energy) and building their skeleton, as well as identifying and stopping invaders. The proteins are made from a chain of amino acids and fold into a three-dimensional structure that gives them stability and allows them to function. Faults in folding, which usually result from a genetic change (mutation), cause them to be unable to perform their function. Accumulation of proteins that have not folded correctly, may sometimes also damage the function of other proteins. Thus, due to malfunctions in protein folding, diseases such as sickle cell anemia, cystic fibrosis and neurological diseases such as Alzheimer’s develop. A better understanding of the mechanism of protein folding may help in the development of drugs for diseases in which it goes wrong.
Prof. Norman Matans from the Faculty of Mathematics and Natural Sciences of the Hebrew University is a chemist who together with his team changes the structure and activity of proteins using chemical methods. This is for the purpose of basic research (for example, examining the relationship between the structure of proteins and their folding and activity), as well as with the aim of finding new ways to cure diseases, for example diabetes and cancer. “When you assemble proteins chemically,” says Prof. Mattans, “you can create changes in them that are not found in nature. For example, we can inject them with amino acids that increase their stability.”
Prof. Matans and his team examine proteins that are produced in cancer cells. They inserted amino acids into these proteins against which inhibitory substances could be developed. In addition, they did this with the protein (which is also a hormone) insulin – which is responsible for balancing the blood sugar level, and introducing it into the body’s cells. The scientists changed a chemical bond between the A and B chains of this protein, thus making it more stable, significantly slowing its rate of degradation, compared to the rate of degradation of the natural protein – while its biological activity remained the same.
In their latest study, which won a grant from the National Science Foundation, the researchers used the hirudin protein, which is a model for protein folding and has been studied extensively in the past. This protein is present in leeches, where it is responsible for inhibiting blood clotting (so that the blood they suck can continue to be liquid and be used to feed them). In the field of medicine, Hirodin is used as a medicine to prevent blood clotting.
The researchers inserted the amino acid selenocysteine into the protein, and asked to know how this would affect its folding, its structure and its activity. They chose selenocysteine because it contains selenium – a mineral they focus on in their lab. Selenium is involved in many vital processes in the human body, among other things it functions as an antioxidant and inflammation, and is obtained through food (it is found in the soil and accumulates in plants from which we feed or in animals that feed from them). It was found that selenium affects the structure of proteins and their folding mechanism, and that its deficiency can cause many diseases, including cancer.
The researchers discovered that the introduction of selenocysteine into hirodin significantly accelerates its folding (minutes instead of hours), and yet, its structure and activity, i.e. its function, do not change and remain normal. “This finding,” says Prof. Matans, “illustrates that the introduction of selenocysteine is a method that can help the rapid and correct folding of many proteins, since hirudin is a model protein that represents them. We know many proteins whose folding is damaged and therefore cause diseases, or drugs that are based on proteins that are difficult to fold correctly. It is possible that if we make this change in other damaged proteins, we will be able to reprogram their folding and thus treat diseases that arise from disruptions in their folding.”
Life itself:
Prof. Norman Matans, 43, was born in the northern village of Marar and currently lives in Jerusalem. Married and father of three children (10, 9, and 1 year old), and in his spare time he likes to spend time with his family.
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