Specific identification and modification of proteins by the N-terminus

Every protein supplies possible information about its natural lifespan: It is found in the amino or N-terminus of the protein. One of the focal points was the proteolytic processes taking place among other things on these N-termini of proteins or involving them, for instance through molecular identification processes. Numerous contributions were about the N-end rule pathway. It states that the N-terminal amino acids may possibly determine the fate and lifespan of the entire protein. A malfunction in this finely regulated balance could be the cause of numerous serious diseases in plants, animals, and humans.

The objective of the organization team consisting of Nico Dissmeyer (Halle), Daniel Gibbs (Birmingham), Emmanuelle Graciet (Maynooth), and Michael Holdsworth (Nottingham) was to hold the first international and interdisciplinary expert conference for post-translational modifications that take place on or through and/or are mediated by the amino-terminus of proteins. Neurodegenerative diseases and new treatments for hepatocellular carcinoma as well plant stress reactions in response to oxygen deficiency and disease were also discussed during “N-Term 2017” under the leading topic of proteostasis.

Mechanisms and phenotypes of N-terminal (faulty) protein regulation

The plenary talks by Professor Dr. Andreas Bachmair of Max F. Perutz Laboratories (MFPL) at the University of Vienna and Professor Dr. Yong Tae Kwon of the Protein Metabolism Medical Research Center at Seoul National University in Korea were highlights of the event. They imparted comprehensive, clear views of historical aspects as well as conceptual novelties in the field. Not only did they elegantly link the balancing act between PTMs in proteasomal protein breakdown versus that by means of autophagy, but also between mechanisms from model systems that could hardly be more dissimilar: yeasts and plants or mammals and mass spectrometry. “Of mice, rats and leaves: Comparative N-terminomics” was the corresponding contribution to the program by Pitter Huesgen (Jülich). In the presentation by Martin Zenker (Magdeburg) for example, the participants had the opportunity to explore human genetic and illness-related details of Johanson-Blizzard syndrome in humans. The conference can be described as truly interdisciplinary in terms of content, which is noteworthy in this field. All current aspects of research were covered by the selection of participants, no matter in what organism context the questions arose.

Strong representation of new interdisciplinary concepts and plant research

As evidenced by the focal points of the contributions, current research in the field of the conference topic mainly revolves around molecular enzymology, biochemistry, and structural biology as well as the significance of proteostasis in a physiological context. Specific topics included the protein aggregation and breakdown of neural protein fragments, human genetics and organ development, protein modifications in the context of programmed cell death, new functions in plant development and adaptation to environmental stresses, and biotechnology and mass spectrometry methods. The plant sciences were slightly overrepresented compared to related disciplines, which led to intensive discussions of the N-end rule in plant signal transduction and plant response to biotic and abiotic stresses.

A link between N-terminal post-translational modifications, in particular argininelization, and autophagy is becoming increasingly clear in the field. This was illustrated by numerous contributions that presented the receptors, substrates, and possible functions of N-terminal argininelization. It was also noted in the course of intensive discussion between the participants that what is known as the N-end rule is far more plastic and complex than long since assumed and also recorded in the literature and textbooks. Many PTMs assumed to be destabilizing have been proven to lead neither to recognition by the molecular “receptors” nor to ultimate proteolysis. Nevertheless, it was agreed that one can speak of a trend, but that not every potentially destabilizing modification has to lead to proteolysis.

Junior scientists have their say

The organizers deliberately invited participants at various career stages to the gathering, thereby creating an atmosphere that enabled discourse across generations. Many group leaders were convinced by the organization team to bring along junior scientists (doctoral candidates, post-docs). This strategy was of course particularly successful in Germany and Europe, but for example also in Korea. Assistance for the travel expenses of the young scientists was provided with funds from the Boehringer Ingelheim Foundation and the Chemical Industry Fund. Over 50% of the more than 100 participants were from abroad and about one quarter came from overseas. A third of the guests from other European countries were doing a doctorate, more than a quarter of all guests were post-docs, and 15 scientists are heads of junior research groups.

The junior scientists took the stage in particular during the talks and poster presentations. Ten of them gave short speeches in addition to their poster presentations to introduce their work, thereby accounting for a quarter of all the presentations. Three poster prizes for the contributions of the students were sponsored by EMBO and Springer Nature, selected from all participants based on their presentation methods, clarity, and experimental approach. The EMBO poster prize went to Mr. Sjon Hartman, Utrecht University (under Professor Rens Voesenek) with the ambiguous title in the plant field “NO problem: ethylene-induced regulation of nitric oxide confers flooding tolerance in plants.” The two book prizes from Springer Nature went to Ms. Leah Taylor-Kearney, University of Oxford (under Dr. Emily Flashman) for the topic of “Conserved Function of a Plant Cysteine Oxidase from Marchantia polymorphia” and to Ms. Su Hyun Lee, Seoul National University (under Professor Yong Tae Kwon) for the topic of “p62 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis.” The methods, problems, and approaches of the winners underscore current trends in the community, where plant research in particular has seen an unprecedented increase in popularity and attention over the last 10 years, and new links between the N-end rule pathway and autophagy were described. A special and lasting achievement is that the first step was taken to lay the foundation for a recurring gathering, with the “N-term baton” being passed to Professor Yong Tae Kwon. He will serve as the lead organizer for “N-term 2019” at Seoul National University in South Korea.

The organizers received considerable support from EU COST Action BM1307: “European network to integrate research on intracellular proteolysis pathways in health and disease (PROTEOSTASIS)” and the German Research Foundation. The DBG provided logistic and financial support as well.

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In November 2017

Dr. Nico Dissmeyer, www.ipb-halle.de und www.dissmeyerlab.org;
Twitter: @NDissmeyer