Menu
Institut de Biologie StructuraleGrenoble / France

Highlights

Chromatin without a twist

Our genetic information is encoded by DNA, which is packaged in the cell nucleus in the form of chromatin. The basic building block of chromatin is the nucleosome, formed by the wrapping of DNA around a core of basic proteins called histones. Nucleosomes pack together to form a nucleosomal array, whose structure is highly dynamic and whose conformation plays a key role in gene expression. Notably, the formation of a compact 30-nm fiber is associated with the inactivation of gene expression. However, how chromatin undergoes a change in conformation remains poorly understood. In collaboration with researchers from Grenoble, Lyon and Strasbourg, IBS researchers investigated the structure of a 6-nucleosome array using a combination of structural, biophysical and biochemical approaches. The 6-nucleosome array forms a surprisingly flat structure, whose nucleosome density is only half that of the 30 nm chromatin fiber. Moreover, a minor change in ionic conditions induces the array to adopt a more compact, twisted conformation that corresponds to that of the 30 nm fiber. These results reveal how a minor change in local environment, generated for example by the post-translational modification of histones, can induce a radical change in chromatin conformation, providing insights into the structural plasticity of chromatin that is central to the regulation of gene expression.

Structure of an H1-bound 6-nucleosome array reveals an untwisted two-start chromatin fiber conformation. Isabel Garcia-Saez, Hervé Menoni, Ramachandran Boopathi, Manu S. Shukla, Lama Soueidan, Marjolaine Noirclerc-Savoye, Aline Le Roy, Dimitrios A. Skoufias, Jan Bednar, Ali Hamiche, Dimitar Angelov, Carlo Petosa, Stefan Dimitrov. Molecular Cell, doi: 10.1016/j.molcel.2018.09.027.

A key step in mitochondrial biogenesis revealed by structural biology

Mitochondria synthesize the adenosine triphosphate (ATP) molecule, which is able to transport chemical energy within cells. The amount of ATP transported daily through the mitochondrial membranes to supply our cells corresponds approximately to our body weight. This transport of mitochondrial ATP is carried out by membrane proteins, produced themselves outside the mitochondria, and which have to be inserted into the membrane where they « work ». Because these membrane proteins are insoluble in cells, their transport is extremely difficult : they may aggregate, which would be a great danger for the cell. Cells have therefore developed carriers of these membrane proteins known as "chaperones". The essential chaperones escort membrane proteins through the intermembrane space, but the structural and mechanistic details remain elusive.
Scientists from the IBS, in collaboration with EMBL, Freiburg and Tübingen Universities in Germany and University of Copenhagen in Denmark, used an integrated structural biology approach to reveal the functional principle of TIM chaperones : multiple clamp-like binding sites hold the mitochondrial membrane proteins before releasing them to their final destination.
These findings, published in Cell on November 15, may be helpful to fight diseases caused by the accumulation of protein molecules, in particular the Mohr-Tranebjærg syndrome, a neurological disorder of deafness and dystonia, caused by a dysfunction of these chaperones. Details can be found on Science Direct and within Freiburg press release.

Structural Basis of Membrane Protein Chaperoning Through the Mitochondrial Intermembrane Space. Katharina Weinhäupl, Caroline Lindau, Audrey Hessel, Yong Wang, Conny Schütze, Tobias Jores, Laura Melchionda, Birgit Schönfisch, Hubert Kalbacher, Beate Bersch, Doron Rapaport, Martha Brennich, Kresten Lindorff-Larsen, Nils Wiedemann, Paul Schanda. Cell 175, 1365–1379

Cécile Morlot is the recipient of the CNRS bronze medal

Cécile Morlot (IBS/Pneumococcus group) is the recipient of a bronze medal of the CNRS 2018. This distinction rewards an on-going and fruitful research activity, which makes him/her a specialist with talent within a particular research field.

During her thesis at the Institute for Structural Biology (IBS) in the group of Thierry Vernet, Cécile developed a fluorescent labelling method to localize, using optical microscopy, proteins in charge of cell division in an important human pathogen : Streptococcus pneumoniae (the pneumococcus). For the first time, these large protein assemblies were visible in the cell at a resolution of a few hundred nanometers. In parallel, she solved the crystallographic structure of one component of these complexes to constrain the model proposed for S. pneumoniae division.
Following her Ph.D. (2003), she completes her training in crystallography as a postdoctoral fellow in the group of Stephen Cusack (EMBL, Grenoble). Next, she enlarges her competences in microbiology during a second postdoctoral internship in the group of David Rudner (Harvard Medical School, Boston), during which she studies two protein complexes involved in spore development in Bacillus subtilis.

She is recruited by the CNRS in 2010 and joins the Pneumococcus group at the IBS to continue her research activities on bacterial morphogenesis and division, using complementary techniques in structural and cellular biology. Her recruitment coincides with the emergence of super-resolution fluorescence microscopy techniques, which allow connecting protein and cellular scales. She decides to develop the use of these techniques in the pneumococcus in collaboration with biophysicists from the IBS (Dominique Bourgeois and Virgile Adam, Pixel team) and a chemist from the University Grenoble Alpes (Yung-Sing Wong, Department of Molecular Pharmacochemistry). The developed methods, based on the localization of single molecules and on "click chemistry", now allow her to image the assembly and activity of protein machineries in charge of cell division at a resolution of about ten nanometers. Because it reveals molecular details that are inaccessible at low resolution, her work in structural biology and cell imaging helps understanding how bacteria acquire their shape and proliferate. This fundamental knowledge is pertinent for the discovery of new antibiotics and for the comprehension of associated resistance mechanisms.