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Andrei Lupas – fascination for the complex world of proteins

Prof. Dr. Andrei Lupas is a molecular biologist and director of the Department of Protein Evolution at the Max Planck Institute (MPI) for Developmental Biology in Tübingen. He became fascinated by the incredible complexity of proteins early on during his scientific career. His work focuses on the use of laboratory and computational methods to solve the question as to how a simple amino acid chain becomes a protein ‘nanomachine’. Lupas and his fellow scientists have developed model systems to study the folding of proteins and their transition into complex systems. Lupas regards the repetition of the basic building blocks as an essential principle without which the complexity of proteins would not be possible.

Biologist Prof. Andrei N. Lupas is a scientific member of the Tübingen-based Max Planck Institute for Developmental Biology, and the director of the institute’s Department of Protein Evolution. © private

As a ten-year-old, Andrei Lupas used to visit the Natural History Museum in his hometown, Bucharest, almost every year, and was soon convinced that he wanted to become a biologist. Following his family’s relocation to Germany, he studied biology at TU Munich. “I actually wanted to become a marine biologist, but I was not keen on leaving my family and I also get seasick easily. So I chose not to study marine biology,” says Lupas who was equally interested in molecular biology. After his preliminary exams, and without the usual diploma degree, Lupas continued his PhD studies in molecular genetics at the University of Princeton. “Back then, it was still possible to do this. PhD students were only required to provide proof that they had passed the equivalent of the American exams,” says Lupas.

Proteins control all processes of life

Lupas discovered his scientific passion – proteins - in the USA: “I found these molecules absolutely fantastic due to their extraordinary complexity and the fact that they have to fold in order to exert their proper function. And I have been studying proteins ever since.”

After more than five years studying molecular biology and carrying out research in the USA, Lupas was awarded his PhD and returned to Germany. He got a job at the Gene Centre at the University of Munich where his work was specifically focused on protein engineering before moving on to the Max Planck Institute for Biochemistry in Martinsried where he focused on the biochemistry and evolution of large protein complexes. He subsequently returned to the USA where he had successfully applied for a position at SmithKline Beecham Pharmaceuticals which had just acquired the data of all sequenced bacterial genomes.

Lupas was put in charge of the antibiotics development where he exclusively used computational methods to study the bacterial genomes from an evolutionary point of view and go on to use this information for developing drug targets. The main objective was to use computational methods to identify pathogenic bacterial protein networks whose chemical activity could be impaired with small molecules.

“I was very excited to have access to all these bacterial genomes for my work. Nobody else had access to them. But I did not really see how these genomes could be converted into money,” says Lupas. “The war between bacteria and fungi has been raging for billions of years and it is safe to assume that nature has extensively tested its targets during this time. Therefore, I was determined from the outset to only stay with the company for five years.” 

Lupas left the American company earlier than planned after accepting a post that he had been offered at the University of Tübingen. He has been a director and scientific member at the Max Planck Institute (MPI) for Developmental Biology since 2001 and also heads up the Department of Protein Evolution. Together with his 35 colleagues, Lupas is now able to focus on experimental work again as well as using complex bioinformatic methods.

Repetition leads to complexity

Research into the complex class of proteins covers a broad field. The scientists from Tübingen are therefore mainly concerned with two essential basic issues: first, they want to find out how a sequence of amino acids becomes a three-dimensional structure, and second, how this structure can become chemically active. “Proteins are basically inert. Collagen for example, has a function, but does not carry out catalyses. I would like to understand how a three-dimensional structure becomes a protein ‘nanomachine’,” says Lupas.

Asked which proteins he is specifically focusing on, Lupas replies: “Theoretically, we can deal with any protein whatsoever. However, it goes without saying that as there are around 1012 naturally occurring proteins, we haven’t got time to experiment with them all. The analysis of one single protein can take years.” This is why the MPI researchers have developed model protein systems: In order to find out how folding occurs, the researchers use bundles of α helices, so-called coiled coils, solenoids or toroids. They use cradle-loop barrels (see Figure) for studying how amino-acid structures evolved into proteins with chemical activity. These model systems are studied using a broad range of experimental approaches including protein chemistry, crystallography and nuclear magnetic resonance.

Schematic showing the evolution of cradle-loop barrels from a primordial peptide into nucleic-acid binding forms with catalytic activity. © Lupas
The biologists from Tübingen presume that when life began on Earth more than 3.5 billion years ago, the first protein building blocks, i.e. peptides, were optimised for a specific function, namely to act as cofactors for the RNA, which served as the first ever protein folding scaffold. As the peptides became more complex, they were able to fold without the support of the RNA scaffold, resulting in the formation of the first proteins. An important principle in the development of proteins was the repetition of the basic building blocks. Lupas refers to this as a fundamental mechanism of biology that is able to produce complexity. “It is not like Lego bricks, where one usually tries to use as many different bricks as possible for building certain objects. The example of immunoglobulins illustrates the principle rather well. The fact that the immunoglobulin genes were amplified led to a system with completely new properties,” says the scientist. “Complexity results from the repetition of components that have already been optimised at a lower evolutionary stage.”

The perfect birthday gift for the committed professor: a personalised protein

On Professor Lupas’ 50th birthday in 2013, his colleagues came up with something very special: They designed a protein that bears his name in the sequence, i.e. a personalised protein structure. "I was totally lost for words," says Lupas commenting on the gift. "To my knowledge, this is the first protein that has been made to encode a name. And it takes a lot of work to do this." It took around four months for the scientists to complete this particular scientific project.

The result was a protein with the amino acid sequence “ANDREINLVPAS“, which was initially inserted into part of a yeast transcription factor. It begins with the amino acid alanine (A) and ends with serine (S). The amino acid uracil (U) was exchanged for the amino acid valine (V), because the letter U (which stands for selenocysteine) can only be produced with difficulty in a biological system.” The protein structure has been published in the Protein Database (PDB) and in the Journal of Structural Biology.*

Asked what he thinks was the most important result of his research work so far, Lupas says: “The hypothesis I am most proud of relates to the idea of how protein folding was achieved in the primordial peptide-RNA world. Protein folding is one of the most basic questions; scientists have focused on solving this puzzle for more than 50 years and I am not sure the puzzle will be solved in my lifetime.”

* Deiss, S., et al. Your personalized protein structure: Andrei N. Lupas fused to GCN4 adaptors. J. Struct. Biol. (2014)

Further information:

Prof. Dr. Andrei N. Lupas
Max Planck Institute for Developmental Biology
Spemannstr. 35
72076 Tübingen
Tel.: +49 (0)7071 601-340
E-mail: andrei.lupas@tuebingen.mpg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/andrei-lupas-fascination-for-the-complex-world-of-proteins