The information below refers to the time of the award.
Elena Conti was born in 1967 in Varese, Italy. She studied chemistry at the University of Pavia and in 1996 received her PhD from the Faculty of Physical Sciences at the Imperial College of Science, Technology and Medicine in London (UK). Conti carried out her post-doctoral work at the Rockefeller University in New York (USA). She returned to Europe in 1999 to set up her own research group at the European Molecular Biology Laboratory (EMBL) in Heidelberg (Germany). In 2006, she was appointed Director and Scientific Member at the Max Planck Institute of Biochemistry in Munich (Germany), where she heads the Department for Structural Cell Biology. Since 2007, she is Honorary Professor at the Ludwig Maximilian University of Munich.
In 2009, Conti has been elected member of the European Molecular Biology Organization (EMBO) and of the German National Academy of Sciences Leopoldina. In recognition of her work, she received several awards, including: in 2005 the Early Career Award of the European Life Science Organization, in 2008 the Gottfried Wilhelm Leibniz Prize of the German Research Foundation (shared with Elisa Izaurralde) and in 2010 the Hans Krebs medal from the Federation of European Biochemical Societies. In 2010 she was bestowed the title of Knight of the Italian National Order of Merit.
Just like we use shredders for destroying documents that contain potentially damaging information or that are no longer used, cells use molecular machines for degrading defective or unneeded macromolecules. Elena Conti has studied the protein complexes that function as cellular nano-machines for shredding RNAs.
RNAs constitute a large family of macromolecules. They are present in all our cells and have multiple functions, such as allowing the translation of genomic information into proteins. Cells have sophisticated quality control systems to recognize RNAs that are either defective or no longer needed, and to swiftly degrade them. Failure in these surveillance systems leads to the accumulation of harmful macromolecules that are damaging to the cells and cause pathologies at the level of the organism.
Conti and her team have solved and visualized the atomic structures of intricate protein complexes caught in the act of marking RNAs (the exon junction complex) and of degrading them (the exosome complex). The results have shown that the molecular mechanisms used by the exosome complex for degrading RNAs are broadly present across different forms of life, and exhibit conceptual similarities with the mechanisms used by the proteasome, the cellular nano-machine that shreds proteins.
“…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.
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.
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).
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.