A graphic of digital computation.
A graphic of digital computation.
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Luigi Vitagliano is paving the way to solving a 60-year-old genetic mystery

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Luigi Vitagliano is paving the way to solving a 60-year-old genetic mystery

His team at the Institute of Biostructure and Bioimaging IBB, in Naples, Italy, are researching how the function of a family of disease-causing proteins has evolved over time

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Being a structural biologist in the age of AlphaFold is like the early days of gold mining. Before this technology, everyone was doing painstaking work on individual gold nuggets, cleaning them and looking at them one by one. Then, all of a sudden, a gold mine appeared. We couldn’t believe our luck. 

For 30 years, I’ve been studying the proteins encoded in our DNA. Within most human cells, there are somewhere between 20,000 and 100,000 different proteins. In certain instances, the way the string of amino acids in a protein takes its shape, also known as 'protein folding' can be full of irregularities, and these are linked to lots of diseases.

Recently, I’ve been looking at a family of human proteins, known as potassium channel tetramerisation domain (KCTD) proteins, that are particularly poorly understood. What is particularly interesting about mutations in these proteins is the range of diseases that they are linked to: from schizophrenia to autism, and leukaemia to colorectal cancers, as well as neurocognitive and movement disorders.

There are 25 KCTD proteins in humans. Around 80% of them seek out other proteins, marking them for degradation and destruction. This process is called ubiquitination, and is essential to keeping cells healthy. As new proteins are being constantly made inside cells, old ones need to be removed. This prevents the build-up of old, defective proteins. It ensures quality control, and maintains a healthy cell cycle within us, to help prevent disease. 

When KCTD proteins don’t work properly, the consequences can be debilitating to our health. However there’s a lot we don’t understand about them, too. Around 20% of KCTD proteins inside cells were mysteries to scientists like me: we had no idea what they do, and therefore how to prevent them mutating and causing disease. Until now, we’ve had very little structural information on them, which has been a major barrier to KCTD research. 

"Entire generations of eminent scientists have been unable to solve this problem – then, almost miraculously, a solution appeared"

The structures predicted by AlphaFold revealed that over the course of evolution their structures have remained very similar despite having very different genetic codes. This was a significant breakthrough. Previously, we’ve relied on genetics to assess the similarities or differences between proteins. Based on genes alone, we thought these proteins would be very different.

Using AlphaFold, we were able to build a new evolutionary family tree based on protein structure rather than genetic sequence. Evolutionary trees are usually built using genetic information, but they don’t take structural similarities into account. Structure relates to function, so using this approach is thrilling – it could reveal all kinds of mysteries about which KCTD proteins have similar functions and how these functions evolved over time.

I used AlphaFold to look at and compare the structure of all 25 KCTD proteins for similarities and differences to identify which parts of these proteins are important. To our delight, the structures appeared to be very accurate.

For example, we already knew that one domain – the BTB domain – was similar amongst all family members, and so we presumed this was the most important part. AlphaFold has revealed far more structural similarities amongst these proteins and has opened up an entirely new realm of exploration. 

For 60 years – including the 30 years that I’ve been working in this field – we’ve tried and failed to find the connection between sequences and structures. Entire generations of eminent scientists have been unable to solve this problem – then, almost miraculously, this solution appeared. All of our data – structural information for all members of the KCTD family – has come from AlphaFold meaning, without it, this study couldn’t have been done at all. 

My feeling was that AlphaFold was a dream. If somebody had told me that in two years we will have over 200 million protein structures, I wouldn’t have believed them. Now, what lies in the decades ahead is finding out exactly what these proteins do. There’s a lot more excitement – a lot more discovery – ahead.