Structure and dynamics of signalling proteins

Group Leader: Pr. Catherine Vénien-Bryan

Many signals in the cell are conveyed by interacting protein molecules. How do protein-protein interactions lead to a response? The most likely explanation is through changes in structure. We study protein-protein interactions in the control of signalling processes using cryo-electron microscopy and combining the results with information from X-ray diffraction and biophysical studies.
 

Ion Channels

The regulation of the flow of potassium ions into cells is important in the propagation of the neuronal action potential, cell volume regulation and muscle contraction. Potassium channels are controlled by pore gating: the channel can exist in either an open or a closed state. Our research is focused on understanding the intimate relationship between ion channel structure and function. The objective is to understand the molecular mechanism at an atomic level.

We are focusing on the inwardly-rectifying family of potassium channels or ‘Kir’ channels, more precisely Kirbac3.1 and human Kir2.1 channel. This project has received funding from the European Union’s Horizon Europe Research and Innovation Program under grant agreement no. 101026386.

We used cryo-electron microscopy to determine the structure of human Kir2.1 channel at high-resolution. By combining structural, in silico, functional and biophysical data, we have determined the impact of a mutation related to a genetic disease (Andersen-Tawil syndrome) on the structure and function of the human Kir2.1 channel.

Protein dynamics and their conformational transitions are essential for most biological functions. To study Kir2.1 channel dynamics, we used normal mode analysis and molecular dynamics simulations to study the conformational changes of this channel and obtain a full understanding of its functioning.

Mutations in Kir2.1 channels are associated with several inherited genetic disorders including  Andersen-Tawil syndrome (ATS), a rare autosomal disorder characterized by developmental skeletal abnormalities and periodic skeletal muscle paralysis. Currently, there is no effective treatment for ATS. Through an integrative approach combining electrophysiology, cryo-EM analysis, and molecular dynamics simulations, we have uncovered the molecular mechanisms by which two specific ATS-causing mutations (R312H and C154Y) disrupt channel function. These finding provide valuable insights that could pave the way for the development of strategies for designing new therapies to restore proper channel activity.

Genome integrity

Genome integrity is maintained with various DNA repair pathways. At the center of the DNA damage Fanconi Anemia repair pathway is the FANCD2/FANCI complex.

We are using cryo electron microscopy and image analysis for studying this complex machinary. Using a combination of molecular biology, cell biology, biochemistry and structural biology, we have identified the fork-like tower domain in the C-terminus of FANCD2 which is required for its complete functions in the DNA interstrand cross-link repair. Interestingly, several disease-causing mutations lie within this region, underscoring the importance of this domain. (collaboration Dr M Cohn, University of Oxford)

Publications

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