Protein-Protein Interactions

Proteins regulate biological processes through a complex network of dynamical interactions. In our team, we address two crucial issues linked to protein interactions:

  • What are the regions at a protein surface that interact with partners?
  • Who interact with whom in the cell?
I have developed JET2, a method exploiting both sequence and structure information to unravel the complxity of protein interfaces associated to different partners and of different origins. JET2 was applied to the whole Protein Bata Bank (predictions available here: JET2Viewer). The method is now being extended to the prediction of protein-DNA binding sites. I showed that the knowledge of a protein's global social behaviour, inferrred from complete cross-docking calculations, informs us on its specific cellular partners. I participated in the development of LISA, a function that estimates protein-protein binding affinities based on density functional theory.

Evolution-based prediction of mutations

The systematic and accurate description of protein mutational landscapes is a question of utmost importance in biology, bioengineering and medicine. We have developed GEMME, an original and fast method that predicts mutational outcomes by explicitely modelling the evolutionary history of natural sequences. It accurately predicts the mutational landscapes of a wide range of protein families, including viral ones and, more generally, of very conserved families. Given an input alignment, it generates the full mutational landscape of a protein in a matter of minutes.

Protein "Infostery"

Deciphering the mechanisms underlying mutational outcomes at the level of the protein structure is very challenging. I am involved in the development of new measures that go beyond classical analyses of protein structural ensembles, in order to extract pertinent biological information in a systematic way. We have developed COMMA and its upgraded version COMMA2 to identify highly sensitive positions in protein structures and predict the effect of mutations by looking at the way residues move and/or fluctuate together.

Evolution and Structural Impact of Alternative Splicing

Alternative splicing greatly contributes to functional diversity in higher eukaryotes by generating multiple transcript isoforms from the same gene. I am in charge of a project (MASSIV ANR-17-CE12-0009, in collab. with H. Richard) that aims at systematically assessing the impact of ASEs on the structure of the procuded isoforms along evolution. We have developed a couple of tools, namely ThorAxe and PhyloSofs, to infer plausible evolutionary scenarios explaining a set of transcripts observed in a set of species and predict the 3D structures of the corresponding isoforms. As a proof-of-concept, we used them to date known functional AS events in the c-Jun N-terminal kinase family and identify residues responsible for AS phenotypic outcome. We further showed a clear link between the functional relevance, tissue-regulation and conservation of AS events on a set of 50 genes. We scaled up the analysis to the whole human protein-coding genome, leading to the identification of a few thousands of conserved AS events.