Elena CONTI
Lauréat du Prix Louis-Jeantet de Médecine 2014

Les informations ci-après se réfèrent à la date de la remise du Prix.

Née en 1967 à Varèse, en Italie, Elena Conti a étudié la chimie à l’Université de Pavie. Après un doctorat obtenu en 1996 à la Faculté des sciences physiques de l’Imperial College of Science, Technology and Medicine de Londres, elle poursuit ses travaux de recherche en tant que post-doctorante à l’Université Rockefeller à New-York. De retour en Europe en 1999, elle crée son propre groupe de recherche au Laboratoire européen de biologie moléculaire à Heidelberg en Allemagne. En 2006, elle est nommée directrice et membre scientifique à l’Institut Max Planck de biochimie à Munich, où elle dirige le département de biologie cellulaire structurale. Depuis 2007, elle est professeur honoraire à l’Université Ludwig Maximilian de Munich.

En 2009, Elena Conti est élue membre de l’Organisation européenne de biologie moléculaire (EMBO) et de l’Académie allemande des sciences Leopoldina. Ses travaux lui ont valu de recevoir plusieurs distinctions prestigieuses parmi lesquelles, en 2005 le prix « Jeune carrière » de l’Organisation européene des sciences du vivant (ELSO), en 2008 le prix « Gottfried Wilhelm Leibniz » de la Fondation allemande pour la recherche (partagé avec Elisa Izaurralde), et en 2010 la médaille Hans Krebs décernée par la Fédération européenne des sociétés de biochimie. En 2010, elle reçoit le titre de Chevalier de l’Ordre du mérite de la République italienne.

Des déchiqueteuses d’ARN

De même que nous utilisons une déchiqueteuse pour détruire des documents contenant des informations préjudiciables ou obsolètes, nos cellules ont recours à des machines moléculaires pour dégrader les macromolécules défectueuses ou inutiles. Elena Conti a étudié les complexes protéiques faisant office de nano-machines cellulaires pour détruire les ARN

Les ARN constituent une grande famille de macromolécules. Présents dans toutes nos cellules, ils ont de multiples fonctions et permettent notamment la traduction des informations génétiques en protéines. Les cellules disposent d’un système sophistiqué de contrôle de qualité leur permettant de reconnaître les ARN défectueux ou superflus et de les dégrader rapidement. Toute faille dans ce système de surveillance conduit à l’accumulation de macromolécules nocives pour les cellules et pouvant entrainer des pathologies pour l’organisme.

Elena Conti et son équipe ont réussi à déchiffrer et à visualiser les structures atomiques de ces complexes protéiques sophistiqués dans leur action de marquage des ARN (complexe de jonction des exons) et de dégradation de ceux-ci (complexe exosome). Leurs travaux ont également permis de montrer que les mécanismes moléculaires utilisés par le complexe d’exosome pour dégrader les ARN se retrouvent largement dans différentes formes de vie et présentent des similarités conceptuelles avec les mécanismes à l’oeuvre dans les protéasomes, les nano-machines cellulaires qui détruisent les protéines.

Visualizing transient molecular machines at atomic resolution

“…machines will be eventually found not only unknown to us but also unimaginable by our mind” wrote Marcello Malpighi more 350 years ago. The seventeenth century Italian anatomist envisioned the human body as composed of machines operating with similar principles as man-made devices. This metaphor is very much topical today, as we think that the life of a cell depends on the workings of protein complexes, molecular machines that are tens of nanometers in size – unimaginable indeed at the time of Malpighi, and even a few decades ago.

To know how a machine operates, one needs to know how it is built. Structural biology of macromolecular complexes is like reverse engineering: it is the process of identifying the principles of how a device operates based on understanding the architecture and properties of the end product. Elena Conti is interested in understanding how protein complexes involved in RNA metabolism operate. These cellular nano-machines are present in low abundance in the cell and are transient in nature, changing in composition and configuration as they perform their functions. Conti and her group use biochemical and biophysical methods to reconstitute protein complexes in defined chemical, functional and structural states. They then use X-ray crystallography to visualize them at nearly atomic resolution, often catching them right as they are carrying out their chemical reactions.

RNA quality control

Generally, eukaryotic RNAs are synthesized as precursors in the nucleus, are then processed and transported to their site of function in the cytosol and eventually get degraded once their task is completed. Elena Conti’s interest in RNA metabolism started with studying the transport factors that export messenger and transfer RNAs from the nucleus to the cytoplasm. Messenger RNAs (mRNAs) contain the information of how new proteins will be built. Errors in these ‘construction plans’ occur frequently in mammalian cells, for example as a result of mutations in the genome and from sporadic mistakes during the production of the mRNAs. Conti has been studying a cellular quality control system that detects and eliminates faulty mRNAs with nonsense mutations, i.e. codons that stop translation prematurely. Her group has elucidated the structures and mechanisms of several key components of the nonsense-mediated mRNA decay (NMD) pathway. In particular, they have studied the mode of action of the exon-junction complex (EJC), an assembly of proteins that serves to detect nonsense codons in the mRNA. Her structural work has shown how the EJC can form a tight grip on the mRNA after it is assembled in the nucleus, how it recruits cytoplasmic NMD factors and how it can be recycled back to the nucleus to start a new round of quality control.

RNA degradation

After a cellular RNA is recognized as faulty, it is rapidly degraded. Conti has been studying the actual process by which RNA is fragmented into its building blocks. In particular, her group has focused on the exosome complex. The exosome is an essential nano-machine that degrades a wide variety of RNAs into single ribonucleotides, processively and directionally. The active core complex of the eukaryotic exosome contains ten protein subunits. Conti and colleagues started by studying a simpler exosome-like complex from archaea. They showed that the archaeal exosome forms a cylindrical, hollow structure with active sites insides, where an RNA substrate could be trapped in the process of being cleaved. Knowledge of the atomic configuration of the archaeal exosome suggested that 9 of the subunits of the eukaryotic exosome would have a similar architecture, but would lack the atoms required for catalytic activity, essentially converting the eukaryotic cylinder into an enzymatically inert cage. Conti and colleagues finally visualized the eukaryotic complex in action: they determined the structure of the entire core complex with an RNA substrate trapped in the central channel of the cylinder, on its way to be degraded by the tenth subunit. Recently, they also determined the structure and mechanisms of the main cytoplasmic regulator of the exosome, the Ski complex. The Ski complex is an assembly that is as large as the core exosome itself and helps to channel RNA substrates into the degradative chamber. This work has allowed Conti and colleagues to formulate the parallels between the RNA-degrading exosome and the polypeptide-degrading proteasome. Although the individual components of these nano-machines and the chemistry of the reactions are unrelated, exosome and proteasome appear to have evolved conceptually similar mechanisms to encage, channel and prepare their substrates for degradation (Figure 1).

The stage is set for Conti and her group to tackle even larger assemblies, trapping both the catalytic and regulatory complexes together, as they interact and coordinate their activities to recognize and degrade specific RNA substrates. Conti will use the Louis-Jeantet Prize money to study such larger nuclear exosome assemblies and how they function in nuclear RNA quality control and processing pathways. The work on the exosome and associated complexes also opens the exciting possibility to develop cell-permeable inhibitors for these cellular machines that might become as useful as proteasome inhibitors and drugs have proved to be.

‘if … I did know the precise structure of the mill, I would understand this motion and action, and if the mill were out of order, I would try to repair the wheels or the damage to their structure’. Marcello Malpighi (from Opera postuma).

19S-20S Proteasome Ski-Exosome

Fig. 1
Parallels in the architecture of the RNA-degrading exosome and the polypeptide-degrading protesome. The schematic representations show the active core complexes: the 10-subunit exosome (Exo-10) on the right and the 20S proteasome on the left. The hollowed cylinders of both complexes (gray and orange) are shown in scale with the central channel highlighted. The catalytically active subunit of the exosome is in purple. The regulatory complexes (in blue) refer to the 19S particle of the proteasome and the Ski complex, a cytoplasmic regulator of the exosome. The drawings also show the possible path of an RNA and polypeptide substrates being channeled to degradation. The schematics are based on current structural and biochemical information. Published in Nature Reviews Molecular Cell Biology (2013) 14: 650-660 and used with permission.

Professor Dr Elena Conti

Director, Structural Cell Biology Department
Max Planck Institute of Biochemistry
Am Klopferspitz 18
D-82152 Martinsried, Munich
Germany

Telephone: +49 89 8578 3602


http://www.biochem.mpg.de/en/rd/conti