Jeff Gelles

Aron and Imre Tauber Professor of Biochemistry and Molecular Pharmacology

Departments/Programs

Biochemistry

Degrees

California Institute of Technology, Ph.D.
Harvard University, B.A.

Expertise

Self-assembly, mechanisms, and regulation of macromolecular machines involved in gene expression and the cytoskeleton. Stochastic processes in single enzyme molecules. Single-molecule light microscopy as a tool to study biochemical mechanisms.

Profile

Living cells are chock full of dynamic complexes of protein, RNA, and DNA molecules. We want to understand the fundamental chemical and physical mechanisms through which these molecular machines perform essential biological processes. Our research is focused in two different areas of study: 1) the function of the molecular machines essential to gene expression and its regulation, in particular those that control the synthesis and processing of messenger RNAs, and 2) the function of molecular machines essential to the organization and utilization of the actin and microtubule cytoskeleton of eukaryotic cells.

All of the processes that we study involve dynamic molecular assemblies and multiple reaction intermediates. It is challenging to study their mechanisms using conventional biochemical approaches because different individual molecules in a population are doing different things at the same time. To overcome this “crowd noise problem”, we have developed and used single-molecule light microscopy methods that allow us to observe the behavior of isolated individual molecules and molecular complexes in real time. Using these techniques we can directly observe the assembly, rearrangements, and disassembly of molecular complexes, characterize conformational changes, and detect biochemical reactions. Together, these methods permit comprehensive investigation of molecular mechanisms, revealing reaction pathways and allowing quantitative evaluation and modeling of reaction dynamics. We perform these single-molecule experiments both in systems reconstituted from purified components and in extracts that recapitulate the molecular complexity of the living cell.

Our research uses approaches from scientific fields ranging from cell biology and genetics through biochemistry and molecular biology to physical chemistry and condensed-matter physics. In our experience, the most exciting advances in science often arise when scientists from different disciplines collaborate. Webpage

Courses Taught

BCBP	200b	Reading in Macromolecular Structure-Function Analysis
BCBP	240a	Advanced Topics in Single-molecule Biophysics
BCHM	103b	Advanced Biochemistry: Cellular Information Transfer Mechanisms
BCHM	145a	How to Decide: Bayesian Inference and Computational Statistics

Awards and Honors

Kazuhito Kinosita Award in Single-Molecule Biophysics, The Biophysical Society (2019)

Member, American Academy of Arts and Sciences (2019)

DeWolf Lecture, Aspen Center for Physics (2017)

Fellow, Radcliffe Institute for Advanced Study (2016 - 2017)

Keynote lecture, Midwest Single-Molecule Workshop (2016)

HHMI-NIBIB Interfaces Award, "Quantitative Biology: A New Curriculum to Link the Physical and Biomedical Sciences" (2006 - 2008)

National Program Chair, 2006 Annual Meeting, The Biophysical Society (2004 - 2006)

NIH MERIT Award (2002 - 2012)

Searle Scholars Award (1990 - 1993)

Lucille P. Markey Scholar in Biomedical Science (1989 - 1994)

Damon Runyon-Walter Winchell Cancer Fund Postdoctoral Fellowship (1987 - 1988)

National Science Foundation Predoctoral Fellowship (1978 - 1981)

Scholarship

Lorraine De Jesús-Kim, Larry J Friedman , Marko Lõoke, Christian K Ramsoomair, Jeff Gelles, Stephen P Bell. "DDK regulates replication initiation by controlling the multiplicity of Cdc45-GINS binding to Mcm2-7." eLife 10. (2021): e65471.

Shashank Shekhar, Gregory J Hoeprich, Jeff Gelles, Bruce L Goode. "Twinfilin bypasses assembly conditions and actin filament aging to drive barbed end depolymerization." J. Cell Biol. 220. (2021): e202006022.

Grace A Rosen, Inwha Baek, Larry J Friedman, Yoo Jin Joo, Stephen Buratowski, Jeff Gelles. "Dynamics of RNA polymerase II and elongation factor Spt4/5 recruitment during activator-dependent transcription." Proc Natl Acad Sci U S A 117. (2020): 32348-32357.

Harden TT, Herlambang KS, Chamberlain M, Lalanne JB, Wells CD, Li GW, Landick R, Hochschild A, Kondev J, Gelles J. "Alternative transcription cycle for bacterial RNA polymerase." Nature Communications 11. (2020): 448.

Champasa K, Blank C, Friedman LJ, Gelles J, Bell SP. "A conserved Mcm4 motif is required for Mcm2-7 double-hexamer formation and origin DNA unwinding." eLife 8. (2019): pii: e45538.

Huang B, Friedman LJ, Sun M, Gelles J, Street TO. "Conformational Cycling within the Closed State of Grp94, an Hsp90-Family Chaperone.." Journal of Molecular Biology 431. 17 (2019): 3312-3323.

Shekhar S, Chung J, Kondev J, Gelles J, Goode BL. "Synergy between Cyclase-associated protein and Cofilin accelerates actin filament depolymerization by two orders of magnitude." Nature Communications 10. (2019): 5319.

Stumper SK, Ravi H, Friedman LJ, Mooney RA, Corrêa IR, et al.. "Delayed inhibition mechanism for secondary channel factor regulation of ribosomal RNA transcription." eLife 8. (2019): e40576.1.

Braun, J.E., Friedman, L.J., Gelles, J. & Moore, M.J. "Synergistic assembly of human pre-spliceosomes across introns and exons." eLife 7. (2018): e37751.

Guo S, Sokolova OS, Chung J, Padrick S, Gelles J, et al.. "Abp1 promotes Arp2/3 complex-dependent actin nucleation and stabilizes branch junctions by antagonizing GMF.." Nature Communications 9. 1 (2018): 2895.

Tetone LE, Friedman LJ, Osborne ML, Ravi H, Kyzer S, Stumper SK, Mooney RA, Landick R, Gelles J.. "Dynamics of GreB-RNA polymerase interaction allow a proofreading accessory protein to patrol for transcription complexes needing rescue.." Proc Natl Acad Sci U S A. 114. 7 (2017): E1081-E1090.

Ticau S, Friedman LJ, Champasa K, Corrêa IR Jr, Gelles J, Bell SP. "Mechanism and timing of Mcm2-7 ring closure during DNA replication origin licensing.." Nat Struct Mol Biol 24. 3 (2017): 309-315.

Chadda R, Krishnamani V, Mersch K, Wong J, Brimberry M, Chadda A, Kolmakova-Partensky L, Friedman LJ, Gelles J, Robertson JL. "The dimerization equilibrium of a ClC Cl(-)/H(+) antiporter in lipid bilayers.." Elife 5. (2016): e17438.

Harden, Timothy T. et al.. "Bacterial RNA Polymerase Can Retain σ70 throughout Transcription." PNAS 113. (2016): 602–7.

Hoskins AA, Rodgers ML, Friedman LJ, Gelles J, Moore MJ.. "Single molecule analysis reveals reversible and irreversible steps during spliceosome activation.." Proc Natl Acad Sci U S A 113. 3 (2016): 602-607.

Bombardier, Jeffrey P. et al.. "Single-Molecule Visualization of a Formin-Capping Protein `decision Complex’ at the Actin Filament Barbed End.." Nature Communications 6. (2015): 8797.

Friedman, L.J. & Gelles, J.. "Multi-wavelength single-molecule fluorescence analysis of transcription mechanisms." Methods 86. (2015): 27-36.

Jansen, Silvia et al.. "Single-Molecule Imaging of a Three-Component Ordered Actin Disassembly Mechanism." Nature Communications 6. (2015): 7202.

Ticau, S., Friedman, L.J., Ivica, N., Gelles, J. & Bell, S.P.. "Single-molecule Studies of Origin Licensing Reveal Mechanisms Ensuring Bidirectional Helicase Loading.." Cell 161. (2015): 513-525.

Paramanathan, T; Reeves, D; Friedman, L; Kondev, J; Gelles, Jeff. "A general mechanism for competitor-induced dissociation of molecular complexes." Nature Communications 5. (2014): 5207.

Smith, B.A., Gelles, J. & Goode, B.L.. "Single-Molecule Studies of Actin Assembly and Disassembly Factors.." Methods in Enzymology. vol. 540 Ed. Vale, R.D.. Academic Press, 2014. 95-117.

Tracy Y. Wang, Larry J. Friedman, Jeff Gelles, Wei Min, Aaron A. Hoskins, and Virginia W. Cornish. "The Covalent Trimethoprim Chemical Tag Facilitates Single Molecule Imaging with Organic Fluorophores." Biophysical Journal 106. 1 (2014): 272-278.

Benjamin A Smith, Shae B Padrick, Lynda K Doolittle, Karen Daugherty-Clarke, Ivan R Corrêa Jr, Ming-Qun Xu, Bruce L Goode, Michael K Rosen, Jeff Gelles. "Three-color single molecule imaging shows WASP detachment from Arp2/3 complex triggers actin filament branch formation." eLife 2. (2013): e01008.

Daniel J.Crawford, Aaron A. Hoskins, Larry J. Friedman, Jeff Gelles, and Melissa J.Moore. "Single-molecule colocalization FRET evidence that spliceosome activation precedes stable approach of 5' splice site and branch site." Proc. Natl. Acad. Sci. 110. 17 (2013): 6783-6788.

Friedman, Larry J., Jeffrey P. Mumm, and Jeff Gelles. "“RNA Polymerase Approaches Its Promoter without Long-Range Sliding along DNA." ” Proceedings of the National Academy of Sciences 110. 24 (2013): 9740-9745.

Inna Shcherbakova, Aaron A. Hoskins, Larry J. Friedman, Victor Serebrov, Ivan R. Correa, Jr., Ming-Qun Xu, Jeff Gelles, and Melissa J. Moore. "Alternative Spliceosome Assembly Pathways Revealed by Single-Molecule Fluorescence Microscopy." Cell Reports 5. 1 (2013): 151-165.

Smith BA, Daugherty-Clarke K, Goode BL, Gelles J. ".Pathway of actin filament branch formation by Arp2/3 complex revealed by single-molecule imaging.." Proc Natl Acad Sci U S A. 110. 4 (2013): 1285.

Breitsprecher D, Jaiswal R, Bombardier JP, Gould CJ, Gelles J, Goode BL.. "Rocket launcher mechanism of collaborative actin assembly defined by single-molecule imaging.." Science 336. 6085 (2012): 1164-1168.

Friedman, Larry F. and Jeff Gelles. "Mechanism of Transcription Initiation at an Activator-Dependent Promoter Defined by Single-Molecule Observation." Cell 148. 4 (2012): 679-689.

Garcia HG, Sanchez A, Boedicker JQ, Osborne M, Gelles J, Kondev J, Phillips R.. "Operator sequence alters gene expression independently of transcription factor occupancy in bacteria." Cell Rep 2. 1 (2012): 150.

Hoskins, Aaron A., Friedman, Larry J., Gallagher, Sarah S., Crawford, Daniel J., Anderson, Eric G., Wombacher, Richard, Ramirez, Nicholas, Cornish, Virginia W., Gelles, Jeff, Moore, Melissa J.. "Ordered and Dynamic Assembly of Single Spliceosomes." Science 331. 6022 (2011): 1289-1295.

Hoskins, Aaron A., Gelles, Jeff, Moore, Melissa J.. "New insights into the spliceosome by single molecule fluorescence microscopy." Current Opinion in Chemical Biology 15. 6 (2011): 864-870.

Sanchez, Alvaro, Osborne, Melisa L., Friedman, Larry J., Kondev, Jane, Gelles, Jeff. "Mechanism of transcriptional repression at a bacterial promoter by analysis of single molecules." The EMBO Journal 30. (2011): 3940-3946.

Ydenberg, Casey A., Smith, Benjamin A., Breitsprecher, Dennis, Gelles, Jeff, Goode, Bruce L.. "Cease-fire at the leading edge: New perspectives on actin filament branching, debranching, and cross-linking." Cytoskeleton 68. (2011): 598-602.

Douglas S. Martin, Reza Fathi, Timothy J. Mitchison, Jeff Gelles. "FRET measurements of kinesin neck orientation reveal a structural basis for processivity and asymmetry." Proc Natl Acad Sci U S A 107. (2010): 5453-5458.

Meghal Gandhi, Benjamin A. Smith, Miia Bovellan, Ville Paavilainen, Karen Daugherty-Clarke, Jeff Gelles, Pekka Lappalainen, Bruce L. Goode. "GMF is a cofilin homologue that binds Arp2/3 complex to stimulate filament debranching and inhibit actin nucleation." Current Biology 20. (2010): 1-7.

Thoresen, T., Gelles, J.. "Processive movement by a kinesin heterodimer with an inactivating mutation in one head." Biochemistry 47. 36 (2008): 9514-21.

Wong, O. K., Guthold, M., Erie, D. A., Gelles, J.. "Interconvertible lac repressor-DNA loops revealed by single-molecule experiments." PLoS Biol 6. 9 (2008): e232.

Crawford, D. J., Hoskins, A. A., Friedman, L. J., Gelles, J., Moore, M. J.. "Visualizing the splicing of single pre-mRNA molecules in whole cell extract." RNA 14. 1 (2007): 170-9.

Subramanian, R., Gelles, J.. "Two distinct modes of processive kinesin movement in mixtures of ATP and AMP-PNP." J Gen Physiol 130. 5 (2007): 445-55.

Dalal, R. V., Larson, M. H., Neuman, K. C., Gelles, J., Landick, R., Block, S. M.. "Pulling on the Nascent RNA during Transcription Does Not Alter Kinetics of Elongation or Ubiquitous Pausing." Mol Cell 23. 2 (2006): 231-9.

Friedman, L. J., Chung, J., Gelles, J.. "Viewing dynamic assembly of molecular complexes by multi-wavelength single-molecule fluorescence." Biophys J 91. 3 (2006): 1023-31.

Mumm, J. P., Landy, A., Gelles, J.. "Viewing single lambda site-specific recombination events from start to finish." Embo J 25. 19 (2006): 4586-95.

Perkins, T. T., Li, H. W., Dalal, R. V., Gelles, J., Block, S. M.. "Forward and reverse motion of single RecBCD molecules on DNA." Biophys J 86. 3 (2004): 1640-8.

Perkins, T. T., Li, H. W., Dalal, R. V., Gelles, J., Block, S. M.. "Forward and reverse motion of single RecBCD molecules on DNA." Biophys J 86. 3 (2004): 1640-8.

Tolic-Norrelykke, S. F., Engh, A. M., Landick, R., Gelles, J.. "Diversity in the rates of transcript elongation by single RNA polymerase molecules." J Biol Chem 279. 5 (2004): 3292-9.

Tolic-Norrelykke, S. F., Engh, A. M., Landick, R., Gelles, J.. "Diversity in the rates of transcript elongation by single RNA polymerase molecules." J Biol Chem 279. 5 (2004): 3292-9.

Yang, W., Gelles, J., Musser, S. M.. "Imaging of single-molecule translocation through nuclear pore complexes." Proc Natl Acad Sci U S A 101. 35 (2004): 12887-92.

Yang, W., Gelles, J., Musser, S. M.. "Imaging of single-molecule translocation through nuclear pore complexes." Proc Natl Acad Sci U S A 101. 35 (2004): 12887-92.

Neuman, K. C., Abbondanzieri, E. A., Landick, R., Gelles, J., Block, S. M.. "Ubiquitous transcriptional pausing is independent of RNA polymerase backtracking." Cell 115. 4 (2003): 437-47.

Hua, W., Chung, J., Gelles, J.. "Distinguishing inchworm and hand-over-hand processive kinesin movement by neck rotation measurements." Science 295. 5556 (2002): 844-8.

Dohoney, K. M., Gelles, J.. "Chi-sequence recognition and DNA translocation by single RecBCD helicase/nuclease molecules." Nature 409. 6818 (2001): 370-4.

Yin, H., Artsimovitch, I., Landick, R., Gelles, J.. "Nonequilibrium mechanism of transcription termination from observations of single RNA polymerase molecules." Proc Natl Acad Sci U S A 96. 23 (1999): 13124-9.

Gelles, J., Landick, R.. "RNA polymerase as a molecular motor." Cell 93. 1 (1998): 13-6.

Vugmeyster, Y., Berliner, E., Gelles, J.. "Release of isolated single kinesin molecules from microtubules." Biochemistry 37. 2 (1998): 747-57.

Wang, M. D., Schnitzer, M. J., Yin, H., Landick, R., Gelles, J., Block, S. M.. "Force and velocity measured for single molecules of RNA polymerase." Science 282. 5390 (1998): 902-7.

Young, E. C., Mahtani, H. K., Gelles, J.. "One-headed kinesin derivatives move by a nonprocessive, low-duty ratio mechanism unlike that of two-headed kinesin." Biochemistry 37. 10 (1998): 3467-79.

Hua, W., Young, E. C., Fleming, M. L., Gelles, J.. "Coupling of kinesin steps to ATP hydrolysis." Nature 388. 6640 (1997): 390-3.

Wang, M. D., Yin, H., Landick, R., Gelles, J., Block, S. M.. "Stretching DNA with optical tweezers." Biophys J 72. 3 (1997): 1335-46.

Berliner, E., Young, E. C., Anderson, K., Mahtani, H. K., Gelles, J.. "Failure of a single-headed kinesin to track parallel to microtubule protofilaments." Nature 373. 6516 (1995): 718-21.

Finzi, L., Gelles, J.. "Measurement of lactose repressor-mediated loop formation and breakdown in single DNA molecules." Science 267. 5196 (1995): 378-80.

Gelles, J., Berliner, E., Young, E. C., Mahtani, H. K., Perez-Ramirez, B., Anderson, K.. "Structural and functional features of one- and two-headed biotinated kinesin derivatives." Biophys J 68. 4 Suppl (1995): 276S-281S; discussion 282S.

Gelles, J., Yin, H., Finzi, L., Wong, O. K., Landick, R.. "Single-molecule kinetic studies on DNA transcription and transcriptional regulation." Biophys J 68. 4 Suppl (1995): 73S.

Yin, H., Wang, M. D., Svoboda, K., Landick, R., Block, S. M., Gelles, J.. "Transcription against an applied force." Science 270. 5242 (1995): 1653-7.

Young, E. C., Berliner, E., Mahtani, H. K., Perez-Ramirez, B., Gelles, J.. "Subunit interactions in dimeric kinesin heavy chain derivatives that lack the kinesin rod." J Biol Chem 270. 8 (1995): 3926-31.

Berliner, E., Mahtani, H. K., Karki, S., Chu, L. F., Cronan, J. E., Jr., Gelles, J.. "Microtubule movement by a biotinated kinesin bound to streptavidin-coated surface." J Biol Chem 269. 11 (1994): 8610-5.

Yin, H., Landick, R., Gelles, J.. "Tethered particle motion method for studying transcript elongation by a single RNA polymerase molecule." Biophys J 67. 6 (1994): 2468-78.

Kuo, S. C., Gelles, J., Steuer, E., Sheetz, M. P.. "A model for kinesin movement from nanometer-level movements of kinesin and cytoplasmic dynein and force measurements." J Cell Sci Suppl 14. (1991): 135-8.

Schafer, D. A., Gelles, J., Sheetz, M. P., Landick, R.. "Transcription by single molecules of RNA polymerase observed by light microscopy." Nature 352. 6334 (1991): 444-8.

Gelles, J., Schnapp, B. J., Sheetz, M. P.. "Tracking kinesin-driven movements with nanometre-scale precision." Nature 331. 6155 (1988): 450-3.

Nilsson, T., Gelles, J., Li, P. M., Chan, S. I.. "Chemical modification of the CuA site affects the proton pumping activity of cytochrome c oxidase." Biochemistry 27. 1 (1988): 296-301.

Schnapp, B. J., Gelles, J., Sheetz, M. P.. "Nanometer-scale measurements using video light microscopy." Cell Motil Cytoskeleton 10. 1-2 (1988): 47-53.

Li, P. M., Gelles, J., Chan, S. I., Sullivan, R. J., Scott, R. A.. "Extended X-ray absorption fine structure of copper in CuA-depleted, p-(hydroxymercuri)benzoate-modified, and native cytochrome c oxidase." Biochemistry 26. 8 (1987): 2091-5.

Blair, D. F., Gelles, J., Chan, S. I.. "Redox-linked proton translocation in cytochrome oxidase: the importance of gating electron flow. The effects of slip in a model transducer." Biophys J 50. 4 (1986): 713-33.

Gelles, J., Blair, D. F., Chan, S. I.. "The proton-pumping site of cytochrome c oxidase: a model of its structure and mechanism." Biochim Biophys Acta 853. 3-4 (1986): 205-36.

Gelles, J., Chan, S. I.. "Chemical modification of the CuA center in cytochrome c oxidase by sodium p-(hydroxymercuri)benzoate." Biochemistry 24. 15 (1985): 3963-72.

Cantley, L. C., Jr., Gelles, J., Josephson, L.. "Reaction of (Na-K)ATPase with 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole: evidence for an essential tyrosine at the active site." Biochemistry 17. 3 (1978): 418-25.

Gelles, J., Klapper, M. H.. "Pseudo-dynamic contact surface areas: estimation of apolar bonding." Biochim Biophys Acta 533. 2 (1978): 465-77.