Researchers from <a href="https://zoll.group.uochb.cz/en">Sebastian Zoll’s group</a> at <a href="https://lcms.labrulez.com/companies/62">IOCB Prague</a> <a href="https://www.nature.com/articles/s41467-023-37988-7">determined</a> the first cryo-EM structures of a surface receptor of the human-infective parasite Trypanosoma brucei gambiense in complex with human complement factor C3 in different conformations. This provides the structural basis to understand how the parasite escapes the immune response at an early stage of infection.
While most pathogens have found ways to avoid the deleterious effects of the immune system by escaping neutralizing antibodies and other effector proteins inside cells or less accessible tissues, African trypanosomes are hiding in plain sight and proliferate within the human blood stream. The parasites are exposed to the full pressure of both branches of the immune system and must employ a plethora of countermeasures to avoid clearance from the cardio-vascular system.
<img src="https://storage.googleapis.com/labrulez-bucket-strapi-h3hsga3/UOCHB_Hagen_Suelzen_Cryo_EM_structures_show_how_Trypanosomes_escape_the_human_innate_immune_response_2_3c995c0aef.jpg" alt="ÚOCHB/Hagen Sülzen: Cryo-EM structures show how Trypanosomes escape the human innate immune response."/>
The mechanisms of this ‘molecular warfare’ have been identified and, particularly with regard to the adaptive immune response, described in detail. However, our understanding of innate immune defence mechanisms had remained incomplete until now.
Under the leadership of Sebastian Zoll, a team of researchers, with Hagen Sülzen as the first author of the study, and including Petr Pompach and Martin Zoltner from BIOCEV, employed an integrative structural biology approach and demonstrated that the interaction between ISG65 and C3, the central hub of the human complement system, is inhibitory and remarkably specific. Inhibiting only a single pathway within the complement system allows the pathogens to maintain a tailored and efficient immune defence.
The study was published in Nature Communications and shows the first 2 cryo-EM structures from IOCB Prague alongside one of the first cryo-EM – Alphafold hybrid models that was deposited to the PDBdev.

Cryo-EM structures show how Trypanosomes escape the human innate immune response

Proteins do not usually form from junk DNA – but if they do and they take hold, they become part of the cell’s protein make-up. They are called de novo proteins because they are practically created out of nothing, anew, and not much is known about them. In a new study published in <a href="https://www.nature.com/articles/s41559-023-02010-2">Nature Ecology &amp; Evolution</a>, researchers from <a href="https://www.biocev.eu/en">BIOCEV</a> and their German colleagues described a large set of these proteins, helping unravel the otherwise hard-to-decipher properties of the mystery proteins.
The human genome is a tangle of DNA strands containing intersecting gene sequences: those that code for functional proteins and those that do not – i.e., non-coding or junk DNA, whose function is still understudied, even though it makes up most of the genome. The advent of modern methods has revealed that even non-coding DNA can carry information needed for the synthesis of proteins, the basic building blocks of the cells of living organisms. A synthesis that was initially unstable, without a specific aim, and purely experimental.
<img src="https://storage.googleapis.com/labrulez-bucket-strapi-h3hsga3/Akademie_ved_Ceske_republiky_Brennen_Heames_and_Filip_Buchel_The_mystery_of_de_novo_proteins_revealed_by_Czech_and_German_researchers_1_df94e4513a.jpg" alt="The Czech Academy of Sciences/Brennen Heames and Filip Buchel: The mystery of de novo proteins revealed by Czech and German researchers."/>
If junk DNA does yield a protein, either of use to the cell or as a harmless experiment, the product takes hold and the so-called de novo protein becomes a permanent part of the cell’s protein make-up. While conventional evolutionary mechanisms work with pre-existing genetic material, these de novo sequences emerge “from scratch” and may not initially have a specific function. The mechanisms of their origin still constitute a great unknown, despite many of these proteins being related to essential life functions and pathological processes.
What are de novo proteins and how are they formed?
A team of researchers from the Faculty of Science at Charles University and the Czech Academy of Sciences, working at the BIOCEV Centre in Vestec near Prague and led by biochemist Klára Hlouchová, joined forces with the group of bioinformatician Erich Bornberg-Bauer from the University of Münster in Germany. The researchers compared 1,800 putative de novo proteins identified in human and fly genomes with 1,800 completely randomly generated protein sequences. The comparison of such sequences may reveal which properties are decisive in the emergence of de novo genes. The study appears in the current issue of the prestigious journal Nature Ecology &amp; Evolution.
<img src="https://storage.googleapis.com/labrulez-bucket-strapi-h3hsga3/Akademie_ved_Ceske_republiky_Brennen_Heames_and_Filip_Buchel_The_mystery_of_de_novo_proteins_revealed_by_Czech_and_German_researchers_2_ee3636c96e.jpg" alt="The Czech Academy of Sciences/Brennen Heames and Filip Buchel: The mystery of de novo proteins revealed by Czech and German researchers."/>
While bioinformatic predictions of biophysical properties do not significantly distinguish between de novo protein sequences and their random counterparts, their experimental characterisation reveals noticeable differences.
De novo proteins exhibit higher solubility, which seems to allow them to integrate better into the cellular environment. “However, this means that sequences with higher structural disorder are preferentially selected during the emergence of de novo proteins,” notes study co-author Filip Buchel, a PhD student at the Faculty of Science of Charles University. “Higher structural content in proteins with no evolutionary history often goes hand in hand with a tendency to form insoluble aggregates that are toxic for cells.”
“All of this suggests that significant selection based on biophysical properties occurs at an early stage of de novo protein evolution,” adds Vyacheslav Tretyachenko, a former PhD student at the Faculty of Science of Charles University (now on a postdoctoral fellowship at the Weizmann Institute of Science in Israel).
The selection of new proteins based on their biophysical properties echoes the selection processes from the dawn of life on Earth that defined the basic properties of early proteins, as the team led by Klára Hlouchová recently published in <a href="https://pubs.acs.org/doi/full/10.1021/jacs.2c12987">J. Am. Chem. Soc.</a>
The large set of proteins required special methods
In this study, the researchers had to adapt traditional biochemical and biophysical characterisation methods to working with the entire set of proteins in order to compare a large number of sequences in parallel. One of the key methods comprised mass spectroscopy, which made it possible to detect individual sequences in the analysed samples. “Working on this project was very exciting because it allowed us to identify proteins that essentially do not exist. It was a proteomic conundrum of sorts,” adds Petr Novák from the Institute of Microbiology of the CAS. The study constitutes the first characterisation of a large set of de novo proteins that has gone beyond purely theoretical research, helping unravel the proteins’ otherwise hard-to-decipher properties.
On the Czech side, the study was supported by the Primus and GAUK grants from Charles University.
<img src="https://storage.googleapis.com/labrulez-bucket-strapi-h3hsga3/Akademie_ved_Ceske_republiky_Brennen_Heames_and_Filip_Buchel_The_mystery_of_de_novo_proteins_revealed_by_Czech_and_German_researchers_3_5d2ca0b9ec.jpg" alt="The Czech Academy of Sciences/Brennen Heames and Filip Buchel: The mystery of de novo proteins revealed by Czech and German researchers."/>

The mystery of de novo proteins revealed by Czech and German researchers

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The Czech Academy of Sciences (CAS) was established by Act No. 283/1992 Coll. as the Czech successor of the former Czechoslovak Academy of Sciences. It is set up as a complex of 54 public research institutions.

Czech Academy of Sciences

The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB Prague) is a leading scientific institution in the Czech Republic, recognized internationally. Its primary mission is basic research in the fields of chemical biology and medicinal chemistry, organic and material oriented chemistry, chemistry of natural compounds, biochemistry and molecular biology, physical chemistry, theoretical chemistry, and analytical chemistry. 

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences

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