Protein conformational flexibility as a general feature for protein organization and dynamics at membrane contact sites – FLEXLINK

Membrane contact sites (MCSs) enable specific lipid exchange between organelles. Our recent results on the archetypical OSBP/VAP complex suggest that the architecture and dynamics of MCS are influenced by intrinsically disordered regions (IDRs). These overlooked structural attributes enable formation of MCS of adjustable thickness and reduce protein crowding. These effects are likely to be general given the abundance of IDRs in MCS proteins. We posit that IDRs guarantee the lateral and/or vertical flexibility of proteins. We will dissect the link between these characteristics and the function, dynamics and organization of MCSs, by using a multidisciplinary and multi-scale approach involving quantitative and super-resolution cell imaging, in vitro reconstitution of membrane systems, structural analysis by cryo-electron tomography, and the development of innovative pharmacological tools. This project will offer new perspectives on the efficiency, plasticity and specificity of MCSs.