Nuclear magnetic resonance (NMR) spectroscopy of human TSPO

TSPO是一种主要位于线粒体膜外膜的跨膜蛋白。TSPO的一个重要特性是，它与多种细胞活动有关，如类固醇激素和血红素的合成、细胞凋亡和细胞增殖。然而，目前还不清楚TSPO如何参与多种细胞活动，以及不同的活动是如何编码的/与TSPO的结构有关。我们假设TSPO的功能多样性与TSPO蛋白参与的不同构象状态和相互作用有关。因此，本项目的目的是通过研究(I)hTSPO与诊断和治疗用的高亲和力配体的相互作用，(Ii)纳米体稳定hTSPO的特定结构状态，(Iii)脂环境对hTSPO结构的影响，以及(Iv)人类A147T多态和基于结构/功能的突变对hTSPO结构和动力学的影响，从而加深我们对hTSPO结构和细胞活性之间关系的理解。对人类TSPO配体依赖结构的高分辨率洞察将有助于开发改进的TSPO特异性配体并更准确地定义蛋白质的细胞活性。

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.