Understanding the faulty proteins linked to cancer and autism

Alphafold helps researchers to discover how protein proteins cause, and how to prevent them

Luigi Vitagliano is a research manager at the Institute of Biocycles and Biomedia in Naples, Italy. His story is shared by Alfafold.

Being a structural biologist in the era of Alphafold resembles the first days of gold mining. Before this technique, everyone was doing a strenuous work to find and clean individual gold nuggets and look at it one by one. Then, suddenly, a golden mine appeared. We could not believe our luck.

For 30 years, I was studying our coded proteins in our DNA. Inside most human cells, there is somewhere between 20,000 and 100,000 different proteins. In some cases, the way the amino acid chain in the protein can be in its shape, also known as “protein fold” full of violations, and this is associated with diseases.

Recently, I have been looking at a family of human proteins, known as Tetramerisation Tetramerisation Canner (KCTD), which are particularly incomprehensible. What causes special attention to mutations in these proteins – caused by genetic mutations – is the scope of diseases associated with them: from schizophrenia to autism, leukemia to colon and rectum cancer, as well as brain and movement disorders.

Since the new proteins are constantly made inside the cells, old or defective cells should be removed. There are 25 types of KCTD proteins in humans, and four fifths are looking for other proteins and a mark for deterioration and destruction. This process is called everywhere and it is necessary to maintain the health of cells and help prevent the disease.

When KCTD proteins do not work properly, the consequences can be a matter of our health. However, there is a lot that we do not understand from them either. About five KCTD proteins inside the cells were secrets for scientists gorgeous: we had no idea what they were doing, and thus how to prevent them from mutating and causing illness. So far, we have had a little structural information on it, which was a great obstacle to KCTD Research.

Alphafold’s structures revealed that throughout the development, its structures remained very similar despite the presence of very different genetic symbols. This was a big penetration. Previously, we relied on genetics to assess similarities or differences between proteins. Based on genes alone, we thought that these proteins would be completely different.

Using Alphafold, we were able to build a new developmental family tree that depends on the shape of these proteins instead of its genetic sequence. Evolutionary trees are usually built using genetic information, but they do not take into account the structural similarities. The structure is related to the function, so using this approach is exciting – it can reveal all types of puzzles that have KCTD proteins that have similar functions and how these functions have evolved over time.

Alphafold has been used to consider and compare the structure of all 25 KCTD proteins for similarities and differences, to determine parts of these important proteins. For our pleasure, the expected Alphafold structures seem very accurate.

For example, we already knew that a part of the KCTD – BTB field – was similar to all family members, so we assumed that this is the most important part. Alphafold has revealed many additional structural similarities between these proteins and opened a completely new world of exploration.

For 60 years – including thirty years in which I worked in this field – we tried and failed to find the relationship between serials and structures. Complete generations of prominent scientists have not been able to solve this problem. Then, almost a miracle, this solution appeared. All our data, structural information for all KCTD family members, came from Alphafold. Without it, it was not possible to do this study at all.

I felt that Alfafold was a dream. If someone tells me that within two years, we will have more than 200 million protein structures, but I couldn’t believe them. Now, what lies in the coming decades is to discover exactly what these proteins do. There is a lot of excitement and discovery.