From the lab: Decoding proteins

Proteins are present in every cell and are the smallest building block of all living beings.

Published:March 27, 2016 12:01 am
It is estimated that about two million different types of proteins are present in the human body. It is estimated that about two million different types of proteins are present in the human body.

By: Ashwani Thakur
IIT Kanpur

Proteins are essential to living organisms. These large molecules, built up of long chains of amino acids, perform several functions that are vital for life. Proteins are present in every cell and are the smallest building block of all living beings. It is estimated that about two million different types of proteins are present in the human body.

Largely, proteins have very well-defined three-dimensional structures. This structure is determined by the sequence of amino acids that make up a protein. Different sequences lead to different three-dimensional structures. It is a very well-known fact that the structure of the protein decides its function. But there is a flip side to this as well since proteins are very delicate molecules. This means that even a small stress like temperature, change of an amino acid, or the ageing of a cell can destabilise their structure and therefore function.

That’s not all. The molecules of the destabilised structure can clump together to form bigger aggregates. These aggregates can destroy cells and choke organs and consequently cause serious diseases of the brain, kidney, heart, spleen and liver. More than 30 such deadly diseases are linked with this phenomenon. Most of these diseases are not curable and there is no drug that can control them. An egg could be used as an analogy to illustrate the loss of functional structure. In its normal state, the egg consists of the yolk and the gelly-like egg-white. But when exposed to a stress, like high temperature, the egg-white coalesces into a solid. Something similar happens to the proteins when they are exposed to stress within our bodies. Their structure gets deformed; they coagulate, make a lump, and gain toxic functions. Scientists have been trying to understand this phenomenon and the nature of coagulation caused by any particular stress condition.

There is another way to understand protein aggregation. Protein-based drugs, called biopharmaceuticals, are produced by genetic engineering approaches. They are produced in large amounts through complex steps of manufacturing and purification. Agitation, temperature, oxidation like stresses play a role in destabilising them to aggregation and a significant fraction of the product can be lost to undesired aggregates.Our team has embarked on a long journey to understand protein aggregation at atomic, molecular, cellular, and organism level. We are using interdisciplinary approaches, ranging from molecular and cell biology to structural biology, to address some of the pressing issues in this area of research.

Whether it is about curing a disease, solving the biopharmaceutical aggregation problem or understanding the design of protein fibers for material application, all these processes are connected to the fundamental understanding of protein structure and the interplay of various forces which holds them.

Subsequently, we are also discovering new therapeutic molecules and evolving new strategies to inhibit or modulate protein aggregation steps. Therapeutic molecules, in some cases, need to reach the brain and for this we have taken nanoscience-based approaches to breach blood-brain barrier, which otherwise do not allow unwanted molecules to pass. Interestingly, there is a brighter side to protein aggregation. The phenomenon happening in the body or under manufacturing conditions can also be reproduced in a test tube with mild perturbation of the protein. We and many other scientists have reported that protein fibers have an ultra-thin, rigid and tough internal structure which is highly stable, just like steel. They have the potential to be modulated to different shapes. Therefore, it is assumed that these protein fibers can be transformed into a variety of protein-based nanostructures with immense material applications.

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