AlphaFold is helping researchers uncover how protein mutations cause disease and how to prevent it.
Luigi Vitagliano is Research Director at the Institute of Biological Structure and Bioimaging in Naples, Italy. He shares the AlphaFold story.
Being a structural biologist in the AlphaFold era is like the early days of gold mining. Before this technology, everyone was doing the hard work of finding, cleaning, and examining individual gold nuggets one by one. Then suddenly a gold mine appeared. We couldn’t believe our luck.
For 30 years I have been studying the proteins encoded in our DNA. Most human cells contain between 20,000 and 100,000 different proteins. In some cases, the way a protein’s amino acid chains are shaped, also known as ‘protein folding’, can be irregular, which is linked to many diseases.
Recently I’ve been looking at a family of human proteins known as KCTD (potassium channel tetramerization domain) proteins, which are particularly poorly understood. What is particularly interesting about mutations in these proteins that occur due to genetic mutations is the range of diseases associated with these proteins, from schizophrenia to autism, leukemia, colon cancer, and brain and movement disorders.
Because new proteins are constantly being made inside cells, old or defective proteins must be removed. There are 25 KCTD proteins in humans, four-fifths of which seek out other proteins and mark them for degradation and destruction. This process is called ubiquitination and is essential for keeping cells healthy and preventing disease.
If the KCTD protein does not function properly, our health can decline as a result. But there’s a lot we don’t understand about them either. About one-fifth of the KCTD proteins inside cells were a mystery to scientists like me. We had no idea what they did and therefore how to prevent them from mutating and causing disease. Until now, we had little structural information about it, and this was a major barrier to KCTD research.
The structures predicted by AlphaFold show that despite the genetic code being very different throughout evolution, the structures have remained very similar. This was a groundbreaking development. Previously, we have relied on genetics to evaluate similarities or differences between proteins. From the genes alone, we thought these proteins would be very different.
Using AlphaFold, we were able to build a new evolutionary family tree based on the shape of the protein rather than its genetic sequence. Evolutionary trees are typically built using genetic information but do not take structural similarities into account. Because structure is related to function, using this approach is thrilling. It could reveal all kinds of mysteries about whether KCTD proteins have similar functions and how these functions evolved over time.
I used AlphaFold to look at the structures of all 25 KCTD proteins and compare their similarities and differences to determine which parts of these proteins are important. To our delight, AlphaFold’s prediction structure turned out to be very accurate.
For example, we already knew that one part of the KCTD protein, the BTB domain, was similar among all family members, so we assumed that this was the most important part. AlphaFold has revealed many additional structural similarities between these proteins and opens up entirely new areas of exploration.
For 60 years, including the 30 years I’ve been working in this field, we’ve tried and failed to find a connection between sequence and structure. Entire generations of eminent scientists have failed to solve this problem. Then, almost miraculously, this solution appeared. All data, structural information for all members of the KCTD family, came from AlphaFold. Without it, this study would not have been possible at all.
My feeling is that AlphaFold was a dream. If someone had told me that in two years we would have over 200 million protein structures, I wouldn’t have believed them. Now the task for the next few decades will be to find out exactly what these proteins do. There will be much more fun and discovery ahead.