Simon Scheuring, Ph.D.

Professor of Physiology and Biophysics

  • Professor of Physiology and Biophysics in Anesthesiology (primary appointment)

212-962-2565

1300 York Avenue, Room E-023
New York, NY 10065


Techniques

Research Areas


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. Lin, YC, Guo, YR, Miyagi, A, Levring, J, MacKinnon, R, Scheuring, S et al.. Force-induced conformational changes in PIEZO1. Nature. 2019;573 (7773):230-234. doi: 10.1038/s41586-019-1499-2. PubMed PMID:31435018 .
  2. Rico, F, Russek, A, González, L, Grubmüller, H, Scheuring, S. Heterogeneous and rate-dependent streptavidin-biotin unbinding revealed by high-speed force spectroscopy and atomistic simulations. Proc. Natl. Acad. Sci. U.S.A. 2019;116 (14):6594-6601. doi: 10.1073/pnas.1816909116. PubMed PMID:30890636 PubMed Central PMC6452689.
  3. Heath, GR, Scheuring, S. Advances in high-speed atomic force microscopy (HS-AFM) reveal dynamics of transmembrane channels and transporters. Curr. Opin. Struct. Biol. 2019;57 :93-102. doi: 10.1016/j.sbi.2019.02.008. PubMed PMID:30878714 .
  4. Pellequer, JL, Parot, P, Navajas, D, Kumar, S, Svetličić, V, Scheuring, S et al.. Fifteen years of Servitude et Grandeur to the application of a biophysical technique in medicine: The tale of AFMBioMed. J. Mol. Recognit. 2019;32 (3):e2773. doi: 10.1002/jmr.2773. PubMed PMID:30565321 .
  5. Heath, GR, Scheuring, S. High-speed AFM height spectroscopy reveals µs-dynamics of unlabeled biomolecules. Nat Commun. 2018;9 (1):4983. doi: 10.1038/s41467-018-07512-3. PubMed PMID:30478320 PubMed Central PMC6255864.
  6. Marchesi, A, Gao, X, Adaixo, R, Rheinberger, J, Stahlberg, H, Nimigean, C et al.. An iris diaphragm mechanism to gate a cyclic nucleotide-gated ion channel. Nat Commun. 2018;9 (1):3978. doi: 10.1038/s41467-018-06414-8. PubMed PMID:30266906 PubMed Central PMC6162275.
  7. Miyagi, A, Scheuring, S. A novel phase-shift-based amplitude detector for a high-speed atomic force microscope. Rev Sci Instrum. 2018;89 (8):083704. doi: 10.1063/1.5038095. PubMed PMID:30184715 .
  8. Ruan, Y, Kao, K, Lefebvre, S, Marchesi, A, Corringer, PJ, Hite, RK et al.. Structural titration of receptor ion channel GLIC gating by HS-AFM. Proc. Natl. Acad. Sci. U.S.A. 2018;115 (41):10333-10338. doi: 10.1073/pnas.1805621115. PubMed PMID:30181288 PubMed Central PMC6187180.
  9. Sumbul, F, Marchesi, A, Takahashi, H, Scheuring, S, Rico, F. High-Speed Force Spectroscopy for Single Protein Unfolding. Methods Mol. Biol. 2018;1814 :243-264. doi: 10.1007/978-1-4939-8591-3_15. PubMed PMID:29956237 .
  10. Takahashi, H, Rico, F, Chipot, C, Scheuring, S. α-Helix Unwinding as Force Buffer in Spectrins. ACS Nano. 2018;12 (3):2719-2727. doi: 10.1021/acsnano.7b08973. PubMed PMID:29390177 .
  11. Miyagi, A, Ramm, B, Schwille, P, Scheuring, S. High-Speed Atomic Force Microscopy Reveals the Inner Workings of the MinDE Protein Oscillator. Nano Lett. 2018;18 (1):288-296. doi: 10.1021/acs.nanolett.7b04128. PubMed PMID:29210266 .
  12. Munguira, ILB, Takahashi, H, Casuso, I, Scheuring, S. Lysenin Toxin Membrane Insertion Is pH-Dependent but Independent of Neighboring Lysenins. Biophys. J. 2017;113 (9):2029-2036. doi: 10.1016/j.bpj.2017.08.056. PubMed PMID:29117526 PubMed Central PMC5685674.
  13. Rigato, A, Miyagi, A, Scheuring, S, Rico, F. High-frequency microrheology reveals cytoskeleton dynamics in living cells. Nat Phys. 2017;13 (8):771-775. doi: 10.1038/nphys4104. PubMed PMID:28781604 PubMed Central PMC5540170.
  14. Uchihashi, T, Scheuring, S. Applications of high-speed atomic force microscopy to real-time visualization of dynamic biomolecular processes. Biochim Biophys Acta Gen Subj. 2018;1862 (2):229-240. doi: 10.1016/j.bbagen.2017.07.010. PubMed PMID:28716648 .
  15. Schillers, H, Rianna, C, Schäpe, J, Luque, T, Doschke, H, Wälte, M et al.. Standardized Nanomechanical Atomic Force Microscopy Procedure (SNAP) for Measuring Soft and Biological Samples. Sci Rep. 2017;7 (1):5117. doi: 10.1038/s41598-017-05383-0. PubMed PMID:28698636 PubMed Central PMC5505948.
  16. Mierzwa, BE, Chiaruttini, N, Redondo-Morata, L, von Filseck, JM, König, J, Larios, J et al.. Dynamic subunit turnover in ESCRT-III assemblies is regulated by Vps4 to mediate membrane remodelling during cytokinesis. Nat. Cell Biol. 2017;19 (7):787-798. doi: 10.1038/ncb3559. PubMed PMID:28604678 PubMed Central PMC5493987.
  17. Colom, A, Redondo-Morata, L, Chiaruttini, N, Roux, A, Scheuring, S. Dynamic remodeling of the dynamin helix during membrane constriction. Proc. Natl. Acad. Sci. U.S.A. 2017;114 (21):5449-5454. doi: 10.1073/pnas.1619578114. PubMed PMID:28484031 PubMed Central PMC5448220.
  18. Rangl, M, Rima, L, Klement, J, Miyagi, A, Keller, S, Scheuring, S et al.. Real-time Visualization of Phospholipid Degradation by Outer Membrane Phospholipase A using High-Speed Atomic Force Microscopy. J. Mol. Biol. 2017;429 (7):977-986. doi: 10.1016/j.jmb.2017.03.004. PubMed PMID:28283404 .
  19. Kisovec, M, Rezelj, S, Knap, P, Cajnko, MM, Caserman, S, Flašker, A et al.. Engineering a pH responsive pore forming protein. Sci Rep. 2017;7 :42231. doi: 10.1038/srep42231. PubMed PMID:28176876 PubMed Central PMC5296754.
  20. Ruan, Y, Miyagi, A, Wang, X, Chami, M, Boudker, O, Scheuring, S et al.. Direct visualization of glutamate transporter elevator mechanism by high-speed AFM. Proc. Natl. Acad. Sci. U.S.A. 2017;114 (7):1584-1588. doi: 10.1073/pnas.1616413114. PubMed PMID:28137870 PubMed Central PMC5320997.
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