Nuclear magnetic resonance (NMR) spectroscopy of human TSPO

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TSPO is a transmembrane protein mainly located in the outer mitochondrial membrane. An important property of TSPO is that it has been linked to several cellular activities such as the synthesis of steroid hormones and heme, apoptosis, and cell proliferation. However, it is currently unclear how it is possible that TSPO is involved in multiple cellular activities and how the different activities are encoded/related to the structure of TSPO. We hypothesize that the functional diversity of TSPO is related to different conformational states and interactions the TSPO protein can engage in. The aim of this project is thus to advance our understanding on the connection between the structure of human TSPO (hTSPO) and its cellular activities by studying (i) the interaction of hTSPO with both diagnostic and therapeutic high-affinity ligands, (ii) the stabilization of specific structural states of hTSPO by nanobodies, (iii) the influence of the lipid environment on hTSPO structure, and (iv) the influence of the human A147T polymorphism as well as structure/function-based mutations on the structure and dynamics of hTSPO. High-resolution insights into the ligand-dependent structure of human TSPO will contribute to the ability to develop improved TSPO-specific ligands and more accurately define the protein’s cellular activities.