Molecular machines are proteins or protein complexes that convert stored or supplied chemical energy into conformational changes to carry out molecular or cellular work. How do the molecular structures and dynamics of protein machines together enable their function? Research efforts in the Deindl laboratory are aimed at addressing this question using a combination of single-molecule fluorescence imaging approaches, structural techniques (primarily X-ray crystallography), biochemistry and computer simulations.
Knowledge of the static architecture of molecular machines alone may not satisfactorily explain how they work. Molecular machines are dynamic in nature and their conformational variability, i.e. the time-dependent fluctuations in their structures, are inherent to their mechanisms and functions.
Single-molecule fluorescence imaging
In order to investigate this dynamic nature, we explore single-molecule fluorescence imaging approaches to directly visualize molecular machines in real time. Their complex dynamics can be difficult to capture in classical bulk experiments since ensemble averaging can obscure the presence of multiple kinetic pathways or transient states. Investigations at the single-molecule level, however, can allow us to directly observe these processes and to correlate structural dynamics with function.
We hope to combine real-time dynamic information from these single-molecule experiments with biochemical and structural data in order to create movies of molecular machines that provide a quantitative and mechanistic understanding of how they work.
Sebastian Deindl, PhD/PI/Associate professor
Martha Schattenhofer, Project Coordinator
Klaus Brackmann, Research Engineer
Guanzhong Mao, Postdoctoral Research Fellow
Pramod Kumar, Postdoctoral Research Fellow
Anton Sabantsev, Postdoctoral Research Fellow
Alan Shaw, Postdoctoral Research Fellow
Brad Van Oosten, Postdoctoral Research Fellow
Oanh Ho, Postdoctoral Research Fellow
Sofia Pytharopoulou, Postdoctoral Research Fellow
Laura Lehmann, PhD-student
Luka Bačić, PhD-student
- Direct observation of coordinated DNA movements on the nucleosome during chromatin remodeling, A. Sabantsev, R.F. Levendosky, X. Zhuang, G. D. Bowman, and S. Deindl, Nature Communications 2019, in press
- C. Lehmann, G. Hewitt, S. Aibara, A. Leitner, E. Marklund, S.L. Maslen, V. Maturi, Y. Chen, D. van der Spoel, J.M. Skehel, A. Moustakas, S. J. Boulton and S. Deindl, Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1, Molecular Cell 2017
- L. Hwang*, S. Deindl*, B.T. Harada and X. Zhuang (*equal contribution)
Histone H4 tail mediates allosteric regulation of nucleosome remodelling by linker DNA, Nature 2014
- Deindl, W.L. Hwang, S.K. Hota, T.R. Blosser, P. Prasad, B. Bartholomew and X. Zhuang, ISWI Remodelers Slide Nucleosomes with Coordinated Multi-Base-Pair Entry Steps and Single-Base-Pair Exit Steps, Cell 2013
- Deindl, T.A. Kadlecek, T. Brdicka, X. Cao, A. Weiss and J. Kuriyan, Structural basis for the inhibition of tyrosine kinase activity of ZAP-70, Cell 2007
- O.S. Rosenberg, S. Deindl, R.J. Sung, A.C. Nairn, J. Kuriyan, Structure of the Autoinhibited Kinase Domain of CaMKII and SAXS Analysis ofthe Holoenzyme, Cell 2005
- Deindl, T.A. Kadlecek, X. Cao, J. Kuriyan and A. Weiss, Stability of an autoinhibitory interface in the structure of the tyrosine kinase ZAP-70 impacts T cell receptor response, PNAS 2009