Simon Scheuring, Ph.D.

Research Summary:

One of the key characteristics of life is the existence of a boundary that delineates the organism from its outer environment. The boundary membrane structure that defines all cells is called the plasma membrane. In eukaryotic cells, membranes also divide the internal space into discrete compartments, organelles, to segregate processes and components. The lipid membrane bilayer serves also as a matrix for a multitude of membrane proteins. The membrane proteins are known to be key molecules for plenty vital cellular functions: transport, energy transduction, signaling, and communication, to name a few. The functional importance of membrane proteins explains why a lot of pathologies are related to disorders at the membrane protein level. Notably ~60% of nowadays drugs target membrane proteins, underlining the medical importance of this class of proteins. Therefore, studies of disorders at the level of membrane proteins and their organisation within the membrane are essential to provide novel strategies for the effective treatment of illness.

At present about 300 unique membrane protein structures have been solved. The difficulty for membrane protein crystallisation is hidden in the amphiphilic nature of these molecules, however technical problems are being overcome by modern crystallisation methods, as visible from the exponential increase of solved structures. Therefore, in future studies the focus shall be shifted onto interaction dynamics, conformational changes and supramolecular complexes of membrane proteins. The final goal being to acquire a dynamic and integrated view of the native bio-membrane. These objectives demand the performance of imaging the membrane at high spatio-temporal resolution, at a high signal-to-noise ratio, in a native-like environment. Unfortunately, to date, this seems impossible…

The atomic force microscope (AFM) fulfils many of the above-mentioned criteria. In particular, the recent development of high-speed atomic force microscopy (HS-AFM) allows now individual molecules to be imaged dynamically in physiological environment. AFM can also be operated in force spectroscopy mode and analyse the physics of the interactions between and within proteins in great detail.

Hence, it is our aim to overcome AFM-related technical and biological bottlenecks to provide first high-resolution dynamic views of complex protein samples, and of membranes extracted from cells and on cells in particular. On the way to there, we aim at gathering a deeper understanding of the structure, conformational changes, the dynamics and interactions within and between protein complexes to get insights into the driving forces that are responsible of higher order organisation and the processes in live cells.

Recent Publications:

1. Pan, S, Gries, K, Engel, BD, Schroda, M, Haselwandter, CA, Scheuring, S et al.. The cyanobacterial protein VIPP1 forms ESCRT-III-like structures on lipid bilayers. Nat Struct Mol Biol. 2024; :. doi: 10.1038/s41594-024-01367-7. PubMed PMID:39060677 .
2. Jiang, Y, Miyagi, A, Wang, X, Qiu, B, Boudker, O, Scheuring, S et al.. HS-AFM single-molecule structural biology uncovers basis of transporter wanderlust kinetics. Nat Struct Mol Biol. 2024;31 (8):1286-1295. doi: 10.1038/s41594-024-01260-3. PubMed PMID:38632360 PubMed Central PMC11490224.
3. Pan, Y, Zhan, J, Jiang, Y, Xia, D, Scheuring, S. A concerted ATPase cycle of the protein transporter AAA-ATPase Bcs1. Nat Commun. 2023;14 (1):6369. doi: 10.1038/s41467-023-41806-5. PubMed PMID:37821516 PubMed Central PMC10567702.
4. Sanganna Gari, RR, Tagiltsev, G, Pumroy, RA, Jiang, Y, Blackledge, M, Moiseenkova-Bell, VY et al.. Intrinsically disordered regions in TRPV2 mediate protein-protein interactions. Commun Biol. 2023;6 (1):966. doi: 10.1038/s42003-023-05343-7. PubMed PMID:37736816 PubMed Central PMC10516966.
5. Lansky, S, Betancourt, JM, Zhang, J, Jiang, Y, Kim, ED, Paknejad, N et al.. A pentameric TRPV3 channel with a dilated pore. Nature. 2023;621 (7977):206-214. doi: 10.1038/s41586-023-06470-1. PubMed PMID:37648856 PubMed Central PMC10584365.
6. Scheuring, S. Forces and energetics of the canonical tetrameric cation channel gating. Proc Natl Acad Sci U S A. 2023;120 (28):e2221616120. doi: 10.1073/pnas.2221616120. PubMed PMID:37399394 PubMed Central PMC10334803.
7. Pan, Y, Pohjolainen, E, Schmidpeter, PAM, Vaiana, AC, Nimigean, CM, Grubmüller, H et al.. Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel. Nat Struct Mol Biol. 2023;30 (4):512-520. doi: 10.1038/s41594-023-00955-3. PubMed PMID:36973509 PubMed Central PMC10194703.
8. Jukic, N, Perrino, AP, Redondo-Morata, L, Scheuring, S. Structure and dynamics of ESCRT-III membrane remodeling proteins by high-speed atomic force microscopy. J Biol Chem. 2023;299 (4):104575. doi: 10.1016/j.jbc.2023.104575. PubMed PMID:36870686 PubMed Central PMC10074808.
9. Jiang, Y, Thienpont, B, Sapuru, V, Hite, RK, Dittman, JS, Sturgis, JN et al.. Membrane-mediated protein interactions drive membrane protein organization. Nat Commun. 2022;13 (1):7373. doi: 10.1038/s41467-022-35202-8. PubMed PMID:36450733 PubMed Central PMC9712761.
10. Sharma, M, Biela, AP, Kowalczyk, A, Borzęcka-Solarz, K, Piette, BMAG, Gaweł, S et al.. Shape-Morphing of an Artificial Protein Cage with Unusual Geometry Induced by a Single Amino Acid Change. ACS Nanosci Au. 2022;2 (5):404-413. doi: 10.1021/acsnanoscienceau.2c00019. PubMed PMID:36281256 PubMed Central PMC9585630.
11. Jiao, F, Dehez, F, Ni, T, Yu, X, Dittman, JS, Gilbert, R et al.. Perforin-2 clockwise hand-over-hand pre-pore to pore transition mechanism. Nat Commun. 2022;13 (1):5039. doi: 10.1038/s41467-022-32757-4. PubMed PMID:36028507 PubMed Central PMC9418332.
12. Falzone, ME, Feng, Z, Alvarenga, OE, Pan, Y, Lee, B, Cheng, X et al.. TMEM16 scramblases thin the membrane to enable lipid scrambling. Nat Commun. 2022;13 (1):2604. doi: 10.1038/s41467-022-30300-z. PubMed PMID:35562175 PubMed Central PMC9095706.
13. Jukic, N, Perrino, AP, Humbert, F, Roux, A, Scheuring, S. Snf7 spirals sense and alter membrane curvature. Nat Commun. 2022;13 (1):2174. doi: 10.1038/s41467-022-29850-z. PubMed PMID:35449207 PubMed Central PMC9023468.
14. Stupka, I, Azuma, Y, Biela, AP, Imamura, M, Scheuring, S, Pyza, E et al.. Chemically induced protein cage assembly with programmable opening and cargo release. Sci Adv. 2022;8 (1):eabj9424. doi: 10.1126/sciadv.abj9424. PubMed PMID:34985943 PubMed Central PMC8730398.
15. Perrino, AP, Miyagi, A, Scheuring, S. Single molecule kinetics of bacteriorhodopsin by HS-AFM. Nat Commun. 2021;12 (1):7225. doi: 10.1038/s41467-021-27580-2. PubMed PMID:34893646 PubMed Central PMC8664958.
16. Tagiltsev, G, Haselwandter, CA, Scheuring, S. Nanodissected elastically loaded clathrin lattices relax to increased curvature. Sci Adv. 2021;7 (33):. doi: 10.1126/sciadv.abg9934. PubMed PMID:34389539 PubMed Central PMC8363152.
17. Sanganna Gari, RR, Montalvo-Acosta, JJ, Heath, GR, Jiang, Y, Gao, X, Nimigean, CM et al.. Correlation of membrane protein conformational and functional dynamics. Nat Commun. 2021;12 (1):4363. doi: 10.1038/s41467-021-24660-1. PubMed PMID:34272395 PubMed Central PMC8285522.
18. Heath, GR, Kots, E, Robertson, JL, Lansky, S, Khelashvili, G, Weinstein, H et al.. Localization atomic force microscopy. Nature. 2021;594 (7863):385-390. doi: 10.1038/s41586-021-03551-x. PubMed PMID:34135520 PubMed Central PMC8697813.
19. Fraser, A, Prokhorov, NS, Jiao, F, Pettitt, BM, Scheuring, S, Leiman, PG et al.. Quantitative description of a contractile macromolecular machine. Sci Adv. 2021;7 (24):. doi: 10.1126/sciadv.abf9601. PubMed PMID:34117062 PubMed Central PMC8195476.
20. Heath, GR, Lin, YC, Matin, TR, Scheuring, S. Structural dynamics of channels and transporters by high-speed atomic force microscopy. Methods Enzymol. 2021;652 :127-159. doi: 10.1016/bs.mie.2021.03.011. PubMed PMID:34059280 .