LAUSR

Translocator protein (TSPO), a mitochondrial membrane protein, has been extensively studied and its role is still debated and continues to be enigmatic. From a structural perspective, despite availability of atomic structures from different species, the possible oligomeric state and its 3D structure remain elusive. In the present study, we attempted to study dynamics of TSPO from the perspective of oligomerization. In this aim, we examined if and how TSPO monomers could assemble to form dimer. Accordingly, we performed several coarse-grained molecular dynamics simulations considering two different initial configurations, one with pair of TSPO monomers distantly placed in a model of bilayer composed of DMPC/cholesterol mixture and the other with preformed dimer models with different starting interactions. We identify stable TSPO dimers with diverse interfaces, some of which being consistent with earlier experimental observations on putative TSPO oligomer interfaces. For most of the stable ones, interactions between aromatic residues were significantly overrepresented in the diverse oligomeric organization. Interestingly, we identified different communication pathways that involve dimer interfaces. Additionally, we observed that a cholesterol molecule in close interaction with TSPO dimer was able to translocate through the bilayer. This phenomenon might be related to the putative mechanism of cholesterol transport, and could be increased and favoured by the dimer formation. Overall, our observations shed new light on TSPO oligomerization and bring new perspectives on its dynamics, as well its interactions with protein and ligand partners.