Faculty

Nils G. Walter

Professor of Chemistry
Professor, Biophysics Research Division

Ph.D., Max-Planck-Institute
Postdoctoral Fellow, University of Vermont

Research Focus: Structural Dynamics and Applications of Non-coding RNAs

Phone: 734.615.2060
E-mail: nwalter@umich.edu
Fax: 734.647.4865

At the interface of Chemistry and Biology, a recent revolution has taken place that has uncovered a plethora of non-coding (nc)RNAs in our bodies, which outnumber protein-coding genes by several-fold, dominate the expression patterns of all genes in all cells, and have inspired entirely new therapeutic intervention approaches.  Our group's goal is to understand the structure-function relationships in these ncRNAs and then utilize them for biomedical, bioanalytical and nanotechnological applications.  The ncRNAs we study range from small RNA catalysts, such as the hammerhead, hairpin and hepatitis delta virus ribozymes with potential use in human gene therapy and relevance to human disease, to large RNA-protein complexes, such as RNA interference machinery involved in gene regulation and virus suppression.  In particular, we employ fluorescence techniques to study in real-time the kinetic mechanisms of these ncRNAs, in bulk solution, in live cells, and at the single-molecule level. Applications include the identification and optimization of ribozymes for gene therapy and as novel biosensors, as well as the characterization of antiviral and antibiotic drugs that target pathogenic RNA function.

Our research by its very nature is highly interdisciplinary, engaging students with a diverse background and providing a broad education. The molecules we study are extremely dynamic over time scales of microseconds to hours. To understand these dynamics we combine state-of-the-art chemical, molecular biological, and biophysical approaches. An outline of several exciting current projects is given below.

1.   Developing a model system for understanding gene silencing by directly observing, using fluorescence techniques, the action of small interfering (si)RNAs and micro (mi)RNAs on pathogenic mRNAs in cell extracts and live cells.

2.   Utilizing single molecule fluorescence imaging techniques to follow movement of the ribosome on a secondary structured mRNA.

3.   Utilizing single molecule fluorescence imaging techniques in nanotechnology to follow autonomously moving engineered "molecular spiders".

4.   Dissecting the mechanism of spliceosome assembly and action in unprecedented detail using recently developed single molecule fluorescence approaches that work in yeast cell extract.

5.   Using single-molecule fluorescence techniques to observe in unprecedented detail fluctuations of single ribozyme molecules between catalytically active and inactive conformations.

Walter Research Group

 

Awards

2015 Jean Dreyfus Boissevain Lecturer 2015, Trinity University, San Antonio, TX
2015 Harold R. Johnson Diversity Service Award, University of Michigan
2010-present Director, Single Molecule Analysis in Real-Time (SMART) Center, University of Michigan
2013 Imes and Moore Faculty Award, College of Literature, Science & the Arts, University of Michigan
2013 Faculty Recognition Award, University of Michigan
2012 Alexander von Humboldt Foundation Visiting Scholar, Johann Wolfgang Goethe University Frankfurt (Harald Schwalbe group)
2011 Election as AAAS Fellow
2011 Selection into the ADVANCE Program for Executive Leadership of the College of LS&A, University of Michigan
2011
Buchanan Lecturer, Bowling Green State University
2006
Visiting Scholar, Harvard University (Sunney Xie group)
2006
Alumnus of the Year Award, Sherbrooke RiboClub
2006 JILA Distinguished Visitor Fellowship
2004
Camille Dreyfus Teacher-Scholar Award
2002
Dow Corning Assistant Professorship - University of Michigan
1996 Otto-Hahn medal for Outstanding Researchers of the Max-Planck Society
1995-1998 Feodor-Lynen Postdoctoral Research Fellowship from the Alexander von Humboldt Foundation
1992-1994 Kekule Ph.D. Scholarship from the Stiftung Stipendienfonds des Verbandes der Chemischen Industrie
1991 Anton Keller Prize for best Chemistry Diploma of the Year at the Technical University of Darmstadt
1989-1991 Study Scholarship from the Studienstiftung des Deutschen Volkes



Representative Publications

  1. Rinaldi, A.J., Lund, P.E.*, Blanco, M.R. and Walter, N.G. (2015) The Shine-Dalgarno sequence of riboswitch-regulated single mRNAs shows ligand-dependent accessibility bursts. Nat. Commun., in press.

  2. Suddala, K.C., Wang, J., Hou, Q. and Walter, N.G. (2015) Mg2+ shifts ligand-mediated folding of a riboswitch from induced-fit to conformational selection. J. Amer. Chem. Soc. 137, 14075-14083.

  3. Blanco, M.R., Martin, J.S., Kahlscheuer, M.L., Krishnan, R., Abelson, J., Laederach, A. and Walter, N.G. (2015) Single molecule cluster analysis dissects splicing pathway conformational dynamics. Nat. Methods 12, 1077-1084

  4. Johnson-Buck, A., Su, X., Giraldez, M.D., Zhao, M., Tewari, M. and Walter, N.G. (2015) Kinetic fingerprinting to identify and count single nucleic acids.  Nat. Biotechnol. 33, 730-732

  5. Fu, J., Yang, Y., Johnson-Buck, A., Liu, M., Liu, Y., Walter, N.G., Woodbury, N.W. and Yan, H. (2014) Multi-enzyme complexes on DNA scaffolds capable of substrate channeling with an artificial swinging arm. Nat. Nanotechnol. 9, 531-536.

  6. Sripathi, K.N., Tay, W.*, Banáš, P., Otyepka, M., Šponer, J. and Walter, N.G. (2014) Disparate HDV ribozyme crystal structures represent intermediates on a rugged folding free energy landscape. RNA 20, 1112-1128.

  7. Pitchiaya, S., Custer, T.C.*, Heinicke, L.A. and Walter, N.G. (2014) Single molecule fluorescence approaches shed light on intracellular RNAs. Chem. Rev. 114, 3224-3265.

  8. Suddala, K.C., Rinaldi, A.J., Feng, J., Mustoe, A.M., Eichhorn, C.D.*, Liberman, J.A., Wedekind, J.E., Al-Hashimi, H.M., Brooks III, C.L. and Walter, N.G. (2013) Single transcriptional and translational preQ1 riboswitches adopt similar pre-folded ensembles that follow distinct folding pathways into the same ligand-bound structure. Nucleic Acids Res. 41, 10462-10475.

  9. Krishnan, R., Blanco, M.R., Kahlscheuer, M.L., Abelson, J., Guthrie, C. and Walter, N.G. (2013) Biased Brownian ratcheting leads to pre-mRNA remodeling and capture prior to first-step splicing.  Nat. Struct. Mol. Biol. 20, 1450-1457.

  10. Ma, J., Liu, Z., Michelotti, N., Pitchiaya, S., Veerapaneni, R., Androsavich, J.R.*, Walter, N.G. and Yang, W. (2013) High-resolution three-dimensional mapping of mRNA export through the nuclear pore. Nat. Commun. 4, 2414, doi:10.1038/ncomms3414.

  11. Todd, G.C.* and Walter, N.G. (2013) Secondary structure of bacteriophage T4 gene 60 mRNA: implications for translational bypassing. RNA, 19, 685-700.

  12. Androsavich, J.R.*, Chau, B.N., Bhat, B., Linsley, P.S. and Walter, N.G. (2012) Disease-linked microRNA-21 exhibits drastically reduced mRNA binding and silencing activity in healthy mouse liver. RNA 18, 1510-1526.

  13. Pitchiaya, S., Androsavich, J.R.* and Walter, N.G. (2012) Intracellular single molecule microscopy reveals time and mRNA dependent microRNA assembly. EMBO rep. 13, 709-715.

  14. Lund, K., Manzo, A.J., Dabby, N., Michelotti, N., Johnson-Buck, A., Nangreave, J., Taylor, S., Pei, R., Stojanovic, M.N., Walter, N.G., Winfree, E. and Yan, H. (2010) Molecular robots guided by prescriptive landscapes. Nature 465, 206-210.

  15. Walter, N.G., Huang, C., Manzo, A.J. & Sobhy, M.A. (2008). Do-it-yourself guide: How to use the modern single molecule toolkit. Nat. Methods 5, 475-489. Editorial comments in Nat. Methods 5 (2008) 457. PMCID: PMC2574008

  16. Al-Hashimi, H.M. and Walter, N.G. (2008) RNA dynamics: it is about time. Curr. Opin. Struct. Biol. 18, 321-329. Editorial comments in Curr. Opin. Struct. Biol. 18 (2008) 279-281.

Click here for a complete list of Dr. Walter's publications

*Indicates a student from the Program in Chemical Biology

 

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