Life Sciences Division

Employing an innovative NMR-based approach, the team managed to successfully characterize the structurally properties of one of these proteins, thereby meeting one of the key challenges in contemporary structural genomics. This breakthrough unlocks the secrets to the ties between structure and function of these intrinsically disordered proteins that play a key role in many human diseases. Full results were published online in the 11 January issue of the Journal of the American Chemical Society.

Structural genomics [2] is grounded in the hypothesis that resolving the 3-dimensional structure of proteins is the key to understanding biological processes in living organisms. However, to date, the techniques employed in structural biology have been unable to identify the 3-dimensional structure of intrinsically disordered proteins (IDPs) [3], which account for around 40% of the proteins coded by the human genome. Many of these proteins are involved in human diseases, such as Tau, which is involved in the development of Alzheimer’s disease, or p53, an important tumour suppressor protein, which is involved in numerous types of cancer. The inability to determine the structure of these proteins, most crucially during functional activity (such as their interactions with multiple partners) made it impossible to decipher a number of essential molecular processes. This is what makes the development of methods for studying the conformational behaviour (4) of IDPs such a central challenge to today’s structural biology community.

Now, a Grenoble-based research team from the CEA’s Life Sciences Division, the CNRS and Joseph Fourier University, working with scientists from the Unit of Virus-Host Cell Interactions [5], has published the first highly-detailed description of the structural and dynamic features of an intrinsically disordered protein: the nucleoprotein of the Sendai virus (a virus similar to the measles virus). This protein plays a crucial role in viral transcriptional and replication inside infected cells. The team achieved this breakthrough feat by pioneering an NMR-based technique. By observing the average chemical shifts in the atom skeleton of the protein, they gained an atomic-level description of the structure of the part of the protein that interacts with its partner (a viral polymerase) to activate viral transcription and replication.

This technique has unlocked possibilities for characterizing a whole range of intrinsically disordered proteins, to gain insight into how they function (or dysfunction) and, ultimately, for developing potential pharmacological inhibitors.

The approach engineered transforms simple spectral data into a model of the structural and dynamic properties of IDPs. The illustration here shows the Sendai virus nucleoprotein, with the active site presenting its partially helical formation.
Credits: CEA

___

Jean-Pierre Ebel Institute of Structural Biology (IBS, three-way CEA-CNRS-Joseph Fourier University institute), Grenoble.
[2] Structural genomics is a new discipline branching out from genomics. Structural genomics seeks to systematically describe the 3-dimensional structure of every protein encoded by a given genome, using biophysical, X-ray crystallography, and NMR-based techniques.
[3] Intrinsically disordered proteins: proteins that are functional despite having no stable 3-dimensional structure
[4] Conformational behaviour: structural and dynamic properties describing the disorder intrinsic to these proteins
[5] Professor Rob Ruigrok, Unit of Virus–Host Cell Interactions (UVHCI), UMI 3265 UJF-EMBL-CNRS Grenoble
[These findings were covered in a joint CEA-CNRS-UJF press release dated 18 January 2010.]