Protein Folding and Misfolded Proteins
By Ritik Ravichandran | 29 August 2024
Proteins are made up of building blocks called amino acids. When these amino are strung up together in different ways, we get different proteins. This level of organisation is known as the primary structure of the protein.
This sequence of amino acids then usually assumes one of two structures.
- A highly coiled slinky like structure known as an alpha helix.
- A sheet like structure known as a beta sheet. This is known as the secondary structure of the protein.
These secondary structures then fold to form compact functional structures. Depending on the function they have to perform, they assume a specific 3D structure. It is this tertiary structure that determines the biological function of the protein. The specific shape allows the protein to interact with other molecules, perform catalytic functions, or provide structural support. It is also important to understand that a misfolding resulting in an erroneous tertiary structure can lead to many diseases.
Protein-folding research began before we knew about diseases caused by protein misfolding. Before 1972, it was believed that infectious diseases were caused by viruses and bacteria. Stanley Prusiner’s research on Creutzfeldt-Jakob disease revealed that misfolded proteins, known as prions, could also be responsible for disease. This discovery changed our understanding of many conditions, showing that protein misfolding is also involved in diseases like Alzheimer’s, Parkinson’s, Huntington’s, and type II diabetes.
What's amazing is that proteins can self-assemble spontaneously and reversibly into their unique native three-dimensional structure under suitable physiological conditions. Here, “spontaneous” means that no external energy source such as ATP hydrolysis is required. This led scientists to believe that it was the amino acid sequence that dictated the way that the protein would fold. In other words, all the information required for a protein to adopt the correct three-dimensional conformation is provided by its amino acid sequence!
In order to make sure that these proteins fold correctly , our body produces another protein called chaperone proteins. Chaperone proteins, also known as molecular chaperones, are proteins that help other proteins fold into their native conformations.
The protein folding problem is something scientists have been working on for years. But what is it? For decades, scientists have tried to find a method to reliably determine a protein’s structure from its sequence of amino acids alone. This grand scientific challenge is known as the protein-folding problem.
AlphaFold, a breakthrough AI software, has been able to make remarkable progress in this area. With AlphaFold we are now able to predict the 3D structure of proteins from their amino acid sequence.
But how has AlphaFold managed to crack the problem that took scientists decades -- in just 4 years? The answer lies in the sheer magnitude of data that AlphaFold can assimilate and process. AlphaFold was taught by showing it the sequences and structures of around 100,000 known proteins. AlphaFold is helping to accelerate research in many fields, including: disease treatment, breaking down single-use plastics, and finding new malaria vaccines.
In essence, understanding protein folding helps us see how proteins do their job and what happens when they don’t. This insight is crucial for understanding and treating diseases caused by misfolded proteins.
References:
- Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. Protein Folding and Processing.
- Dobson, C. M. Protein folding and misfolding. Nature 426, 884–890 (2003)
- Dobson, C. M. Protein misfolding diseases: Getting out of shape. Nature 418, 729–730 (2002)
- Jumper, J., Evans, R., Pritzel, A. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021)