Alphafold helps researchers uncover how protein disruptions cause disease and how to prevent them
Luigi Vitagliano is the research director at the Institute for Anatomy and Bioimaging in Naples, Italy. He shares the story of the Alphafold.
Being a structural biologist in the Alphafold era is like the early days of gold mining. Before this technology, everyone had a hard work to find individual gold nuggets. Then, a gold mine suddenly appeared. We couldn’t believe in our luck.
For 30 years I have been studying DNA-encoded proteins. Within most human cells there are 20,000 to 100,000 different proteins. In certain instances, the way in which the strings of amino acids in a protein take their shape is also known as “protein folding” is full of irregularities, and these are associated with many diseases.
Recently, I have seen a particularly well-understood family of human proteins known as potassium channel tetramerization domain (KCTD) proteins. Of particular interest about mutations in these proteins is the range of diseases that are caused by genetic mutations – from schizophrenia to autism, leukemia, brain and motor disorders.
New proteins are always produced intracellularly, so old or defective proteins need to be removed. Humans have 25 different KCTD proteins, four-fifths of which search for other proteins and mark them for degradation and destruction. This process is called ubiquitination and is essential to help keep cells healthy and prevent disease.
If KCTD proteins do not function properly, the results can be debilitating in our health. But there are many things I don’t understand about them either. About a fifth of the intracellular KCTD proteins were a mystery to scientists like me. We didn’t know what they were doing. Until now, there was little structural information about them, but this was a major barrier to KCTD studies.
The structures predicted by Alphafold revealed that over the course of evolution, despite having very different genetic codes, their structures are very similar. This was a big breakthrough. Previously, we relied on genetics to assess similarities or differences between proteins. Based solely on genes, we considered these proteins to be very different.
Using Alphafold, we were able to construct new evolutionary family trees based on the shape of these proteins rather than genetic sequences. Evolutionary trees are usually constructed using genetic information, but do not take into account structural similarities. Using this approach is thrilling, as structures are functionally relevant. This could reveal all sorts of mystery about which KCTD proteins have similar functions and how these functions evolve over time.
Using AlphaFold, we investigated and compared the structures of all 25 KCTD proteins for similarity and differences to determine which portions of these proteins were important. For our pleasure, the predicted structure of Alphafold appeared to be very accurate.
For example, we presumed that this was the most important part, as we already knew that one section of the KCTD protein (the BTB domain) was similar among all families. Alphafold revealed more additional structural similarities between these proteins, opening up an entirely new area of exploration.
For 60 years, including 30 years I have worked in this field, we have tried to find a connection between sequences and structures. An entire generation of well-known scientists could not solve this problem. After that, almost miraculously, this solution appeared. All data, structural information for all members of the KCTD family, comes from Alphafold. Without it, this study would not have been possible at all.
My feelings were that Alphafold was a dream. If someone had said two years later they had over 200 million protein structures, I wouldn’t believe them. Well, what we’ll be doing in the next few decades is finding exactly what these proteins do. There is more excitement and discovery ahead.
