Magic of protein architecture
Proteins after their synthesis get a rigid three dimensional conformation and become capable to carry out catalytic activities
Proteins are, simply, the product of genes. Genes, the basic unit of information for the living systems, are the guide to create thousands of different types of proteins in a particular cell type to enable the cell to carry out its assigned function. It is the protein molecule that makes the different cell types different by having been created in certain combinations in a cell type specialized to perform a particular task. Hence, we get our arms, legs, eyes different from one another. Scientists, for long, have believed that the proteins need to have a rigid structure to play their roles inside the cell. In fact, the biochemistry text books will tell you that the genes encode proteins, which are simply the chain of different amino acids linked together by peptide bonds and after the formation of the polypeptide chains, they need to get a definite three dimensional shape which will react with the target molecules by lock-and-key system. However, recent research is revealing a new architectural design of the proteins. A host of proteins carry out their biological tasks without ever completely folding; others fold only as needed. Perhaps one third of all human proteins are intrinsically disordered carrying some unfolded or disordered regions. Hundred years back, scientists knew that many antibodies, one type of protein of the immune system, can bind to multiple targets which is the obvious deviation from the strict lock-and-key model. In the 1940s, this concept of the deviation from the previously known model was strengthened. From then on, various observations showed that not every protein follows the dogma that proteins' functions require a rigid three dimensional structure. However, proteins showing deviations from the dogma was considered as freak exceptions to the rule. But through several observations from some scientists it was evident that the dogma itself needed some revision. In 1953 scientists noticed that milk protein casein is largely unstructured, that is not folded properly and it probably helps in digestion for the infants. In the 1970s, a part of fibrinogen protein was found unstructured (which plays crucial role in blood clotting). In 1996, Kriwacki et al; performed NMR (Nuclear Magnetic Resonance) spectroscopy on p21, a protein involved in the control of cell division and hence an important player in preventing cancer. The group found something shocking. The p21 protein was almost entirely disordered, changing itself from one conformation to another within fraction of a second. However, it was able to carry out its normal regulatory function- this was the shocking part of their observation. This was the first demonstration that lack of folding does not make a protein useless. Indeed, NMR, together with other technologies has confirmed that many proteins are intrinsically unstructured and they constantly change their conformation and still they are perfectly functional. Calcineurin, a protein of the immune system, removes phosphates from particular proteins having phosphate group attached already. The functional site of the Calcineurin performs this task in a lock and key manner. But it also has an unstructured region which self regulates the protein's catalytic activity. Until recently, around six hundreds partially or totally unstructured proteins have been identified and likely many more to come in the scenario. The investigators have found that roughly 35 percent of human proteins have long unstructured regions and deviate from the lock and key dogma. It is now clear that a combination of these two types of proteins are necessary to carry out normal function in a living being where the rigidly structured ones are mostly involved in enzymatic activity and the unstructured ones are specialized for signaling and regulation. Moreover, the intrinsically disordered proteins can be involved in certain diseases and might be a target for drug discovery. Many laboratories are working to find a treatment for cancer, retinoblastoma and many other diseases. Surely, the detailed study of the partially or fully unstructured proteins along with the rigid ones will help better understand life and living processes.
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