Prof. Dr. Robert Tampé
Goethe University, Institute of Biochemistry, Cellular Biochemistry
1. PhD project:
Transmembrane signaling by dynamic in-situ receptor confinement
Cell-cell communication is crucial for multicellular organisms and relies on the dynamic assembly of receptor-ligand complexes at the plasma membrane. Receptor clustering is a key process in signal transduction and pleiotropic downstream cell responses. Heterotrimeric G protein-coupled receptors (GPCRs) are members of a large family of membrane proteins, which mediate a myriad of cellular processes. The physiological relevance of receptor clustering or confinement is, however, poorly understood. In this proposal, we aim to control the membrane organization of GPCRs in-situ and reveal how location, lateral diffusion, density, and confinement of receptors modulate early signaling events and the final physiological outcome. Our integrative approach, using small synthetic photo-activatable lock-and-key pairs, photo-instructive matrices, and G protein sensors, brings us in the unique position to study receptor clustering in living cells. We aim at a cutting-edge combination of (opto)chemical biology, membrane biochemistry, cellular biophysics, and imaging techniques to decode the mechanism underlying GPCR activation by confinement and downstream signaling by confinement.
2. PhD project:
Coping with daily invaders, our adaptive immune system depends on cell surface presentation of the host proteome in the form of proteasomal degradation snippets on major histocompatibility class I (MHC I). Antigen processing is orchestrated in the ER by a highly dynamic, multi-subunit peptide loading complex (PLC). However, the subcellular architecture and hierarchical organization of this machinery remains enigmatic. Nanoscale compartmentalization of PLCs forms the structural foci, which evoke cellular responses and are the prime target during viral infection. One of the unmet needs is to uncover the nanoscale compartmentalization of the PLC within professional antigen-presenting cells such as primary dendritic cells (DCs). The nanoscale analysis of the subcellular distribution of the antigen processing machinery in DCs will unravel the molecular underpinning of antigen presentation. To this aim, new fluorescence imaging modalities, including expansion and super-resolution microscopy, and advanced labeling techniques are needed to decipher the supramolecular organization of the antigen processing machinery. This PhD project aims to resolve the subcellular localization and hierarchical organization of PLC nanodomains as well as their individual constituents during viral infection. You will develop approaches to image and manipulate the remodeling of molecular complexes in-situ in a 3D cellular context.
References to the first and second PhD project:
1) Sánchez MF, Tampé R (2022) Ligand-independent receptor clustering modulates transmembrane signaling: a new paradigm. Trends Biochem Sci, in press. doi:10.1016/j.tibs.2022.08.002
2) Sušac L, Yuong MT, Thomas C, von Bülow S, O’Brien-Ball C, Santos AM, Fernandes RA, Hummer G, Tampé R*, Davis SJ* (2022) Structure of a fully assembled tumor-specific T-cell receptor ligated by pMHC. Cell 185, 3201-13. doi:10.1016/j.cell.2022.07.010 (Research Highlight in Nat Struct & Mol Biol, Science Immunology, Cancer Discovery)– IF 41.6
3) Sánchez MF, Els-Heindl S, Beck-Sickinger AG, Wieneke R, Tampé R (2021) Photo-induced receptor confinement drives ligand-independent GPCR signaling. Science, eabb7657. doi:10.1126/science.abb7657 (Research Highlight in Nature Chemical Biology; Highlight in Faculty 1000 Recommended 9.8) – IF 41.8
4) Hofmann S, Januliene D, Mehdipour AR, Thomas C, Stefan E, Brüchert S, Kuhn BT, Geertsma ER, Hummer G, Tampé R*,#, Moeller A* (2019) Conformation space of a heterodimeric ABC exporter under turnover conditions. Nature 471, 580-3. doi:10.1038/s41586-019-1391-0
(Front Cover Story in Nature 2019) – IF 42.8
5) Blees A, Januliene D, Hofmann T, Koller N, Schmidt C, Trowitzsch S, Moeller A, Tampé R (2017) Structure of the human MHC-I peptide-loading complex. Nature 551, 525-8. doi:10.1038/nature24627 (Front Cover Story and News & View in Nature 2017; Dispatch in Current Biology 2018; Highlight in F1000 2018; Viewpoint in Mol Immunol 2018; Most Cited Paper in Web of Science. – IF 42.8
6) Thomas C, Tampé R (2017) Structure of the TAPBPR-MHC I complex defines the mechanism of peptide loading and editing. Science 358, 1060-4. doi:10.1038/nature24627
(Insights and Perspectives in Science 2017; News & View in Nature 2017; Highlight in F1000 2018; Viewpoint in Biochemistry 2018) – IF 41.8