Table of Contents
I Introduction and Commentaries 1
1 Image Formation, Optical Diffraction, and Digital Image Processing 3
2 Development of Methods for 2D Averaging and 3D Reconstruction of Biological Macromolecules 6
3 Focus Shifting from Methodology to Biology: the Ribosome and the Mechanism of Translation 11
3.1 Discoveries related to ribosome structure 11
3.2 The need for additional tools 15
3.3 Discoveries shedding light on ribosome dynamics 18
4 The "Resolution Revolution" 19
4.1 Impact on ribosome research 20
4.2 Foray into channel structures and their gating mechanisms 21
5 Adding the Dimension of Time 21
5.1 Time-resolved cryo-EM 21
5.2 The Free-Energy Landscape: mapping continuous changes in conformation 22
6 Oudook 23
7 Acknowledgments 23
8 Comprehensive List of Original Publications 24
II Reprints of Selected Articles, in Chronological Order 41
1 Frank, J. (1969). (in German) Nachweis von Objektbewegungen im lichtoptischen Diffraktogramm von elektronenmikroskopischen Aufnahmen [Detection of object movement in the optical diffractograms of electron micrographs]. Optik 30: 171-178. [Translated version of paper included.] 43
2 Frank, J. (1973). The envelope of electron microscopic transfer functions for partially coherent illumination. Optik 38: 519-536. 51
3 Frank, J. (1975). Averaging of low exposure electron micrographs of non-periodic objects. Ultramicroscopy 1: 159-162. 69
4 Frank, J., and Al-Ali, L. (1975). Signal-to-noise ratio of electron micro-graphs obtained by cross correlation. Nature 256: 376-378. 73
5 Saxton, W.O., and Frank, J. (1977). Motif detection in quantum noise-limited electron micrographs by cross-correlation. Ultramicroscopy 2: 219-227. 76
6 Frank, J., Goldfarb, W., Eisenberg, D., and Baker, T.S. (1978). Reconstruction of glutamine synthetase using computer averaging. Ultramicroscopy 3: 283-290. 85
7 Frank, J., Shimkin, B., and Dowse, H. (1981). SPIDER - A modular software system for electron image processing. Ultramicroscopy 6: 343-357. 94
8 Frank, J., Verschoor, A., and Boublik, M. (1981). Computer averaging of electron micrographs of 40S ribosomal subunits. Science 214: 1353-1355. 109
9 van Heel, M., and Frank, J. (1981). Use of multivariate statistics in analysing the images of biological macromolecules. Ultramicroscopy 6: 187-194. 112
10 Frank, J., and van Heel, M. (1982). Correspondence analysis of aligned images of biological particles. J. Mol. Biol. 161: 134-137. 120
11 Bretaudiere, J.-P., and Frank, J. (1986). Reconstitution of molecule images analysed by correspondence analysis: a tool for structural interpretation. J. Microsc. 144: 1-14. 124
12 Radermacher, M., Wagenknecht, T., Verschoor, A., and Frank, J. (1987). Three-dimensional reconstruction from a single-exposure, random conical tilt series applied to the 50S ribosomal subunit of Escherichia coli. J. Microsc. 146: 113-136. 138
13 Verschoor, A., and Frank, J. (1990). Three-dimensional structure of the mammalian cytoplasmic ribosome. J. Mol. Biol. 214: 737-749. 162
14 Penczek, P., Radermacher, M., and Frank, J. (1992). Three-dimensional reconstruction of single particles embedded in ice. Ultramicroscopy 40: 33-53. 175
15 Srivastava, S., Verschoor, A., and Frank, J. (1992). Eukaryotic initiation factor 3 does not prevent association through physical blockage of the ribosomal subunit-subunit interface. J. Mol. Biol. 226: 301-304. 196
16 Penczek, P.A., Grassucci, R.A., and Frank, J. (1994). The ribosome at improved resolution: new techniques for merging and orientation refinement in 3D cryo-electron microscopy of biological particles. Ultramicroscopy 53: 251-270. 200
17 Frank, J., Zhu, J., Penczek, P., Li, Y., Srivastava, S., Verschoor, A., Radermacher, M., Grassucci, R., Lata, R.K., and Agrawal, R.K. (1995). A model of protein synthesis based on cryo-electron microscopy of the E. coli ribosome. Nature 376: 441-444. 221
18 Agrawal, R.K., Penczek, P., Grassucci, R.A., Li, Y., Leith, A., Nierhaus, K.H., and Frank, J. (1996). Direct visualization of A-, P-, and E-site transfer RNAs in the Escherichia coli ribosome. Science 271: 1000-1002. 225
19 Beckmann, R., Bubeck, D., Grassucci, R., Penczek, P., Verschoor, A., Blobel, G., and Frank, J. (1997). Alignment of conduits for the nascent polypeptide chain in the ribosome-Sec61 complex. Science 278: 2123-2126. 228
20 Penczek, P.A., Zhu, J., Schröder, R., and Frank, J. (1997). Three dimensional reconstruction with contrast transfer compensation from defocus series. Scanning Microsc. 11: 147-154. 232
21 Agrawal, R.K., Penczek, P., Grassucci, R.A., and Frank, J. (1998). Visualization of elongation factor G on the Escherichia coli 70S ribosome: the mechanism of translocation. Proc. Natl. Acad. Sci. USA 95: 6134-6138. 240
22 Ban, N., Freeborn, B., Nissen, P., Penczek, P., Grassucci, R.A., Sweet, R., Frank, J., Moore, P.B, and Steitz, T.A. (1998). A 9Å resolution X-ray crystallographic map of the large ribosomal subunit. Cell 93: 1105-1115. 245
23 Gabashvili, I.S., Agrawal, R.K., Spahn, C.M.T., Grassucci, R.A., Svergun, D.L, Frank, J., and Penczek, P. (2000). Solution structure of the E. coli 70S ribosome at 11.5Å resolution. Cell 100: 537-549. 256
24 Frank, J., and Agrawal, R.K. (2000). A ratchet-like inter-subunit reorganization of the ribosome during translocation. Nature 406: 318-322. 269
25 Beckmann, R., Spahn, C.M.T., Eswar, N., Helmers, J., Penczek, P.A., Sali, A., Frank, J., and Blobel, G. (2001). Architecture of the protein-conducting channel associated with the translating 80S ribosome. Cell 107: 361-372. 274
26 Spahn, C.M.T., Beckmann, R., Eswar, N., Penczek, P.A., Sali, A., Blobel, G., and Frank, J. (2001a). Structure of the 80S ribosome from Saccharomyces cerevisiae - tRNA-ribosome and subunit-subunit interactions. Cell 107: 373-386. 286
27 Spahn, C.M.T, Kieft, J.S., Grassucci, R.A., Penczek, P.A., Zhou, K., Doudna, J.A., and Frank, J. (2001b). Hepatitis C virus IRES RNA-induced changes in the conformation of the 40S ribosomal subunit. Science 291: 1959-1962. 300
28 Valle, M., Sengupta, J., Swami, N.K., Grassucci, R.A., Burkhardt, N., Nierhaus, K.H., Agrawal, R.K., and Frank, J. (2002). Cryo-EM reveals an active role for aminoacyl-tRNA in the accommodation process. EMBO J. 21: 3557-3567. 304
29 Gao, H., Sengupta, J., Valle, M., Korostelev, A., Eswar, N., Stagg, S.M., Van Roey, P., Agrawal, R.K., Harvey, S.C., Sali, A., Chapman, M.S., and Frank, J. (2003). Study of the structural dynamics of the E. coli 70S ribosome using real-space refinement. Cell 113: 789-801. 318
30 Rawat, U.B.S., Zavialov, A.V, Sengupta, J., Valle, M., Grassucci, R.A., Linde, J., Vestergaard, B., Ehrenberg, M., and Frank, J. (2003). A cryo-electron microscopic study of ribosome-bound termination factor RF2. Nature 421: 87-90. 331
31 Valle, M., Gillet, R., Kaur, S., Henne, A, Ramakrishnan, V., and Frank, J. (2003). Visualizing tmRNA entry into a stalled ribosome. Science 300: 127-130. 335
32 Valle, M., Zavialov, A., Li, W., Stagg, S.M., Sengupta, J., Nielsen, R.C., Nissen, P., Harvey, S.C., Ehrenberg, M., and Frank, J. (2003). Incorporation of aminoacyl-tRNA into the ribosome as seen by cryo-electron microscopy. Nat. Struct. Biol. 10: 899-906. 339
33 Valle, M., Zavialov, A., Sengupta, J., Rawat, U., Ehrenberg, M., and Frank, J. (2003). Locking and unlocking of ribosomal motions. Cell 114: 123-134. 347
34 Yarus, M., Valle, M., and Frank, J. (2003). A twisted tRNA intermediate sets the threshold for decoding. RNA 9: 384-385. 359
35 Spahn, C.M.T., Gomez-Lorenzo, M.G., Grassucci, R.A., Jørgensen, R., Andersen, G.R., Beckmann, R., Penczek, P.A., Ballesta, J.P.G., and Frank, J. (2004). Domain movements of elongation factor eEF2 and the eukaryotic 80S ribosome facilitate tRNA translocation. EMBO J. 23: 1008-1019. 361
36 Allen, G.S., Zavialov, A., Gursky, R., Ehrenberg, M., and Frank, J. (2005). The cryo-EM structure of a translation initiation complex from Escherichia coli. Cell 121: 703-712. 373
37 Gao, H., Ayub, M.J., Levin, M.J., and Frank, J. (2005). The structure of the 80S ribosome from Trypanosoma cruzi reveals unique rRNA components. Proc. Natl. Acad. Sci. USA 102: 10206-10211. 383
38 Penczek, P.A., Yang, C., Frank, J., and Spahn, C.M.T. (2006). Estimation of variance in single-particle reconstruction using the bootstrap technique. J. Struct. Biol 154: 168-183. 389
39 Frank, J., Gao, H, Sengupta, J., Gao, N., and Taylor, D.J. (2007). The process of mRNA-tRNA translocation. Proc. Nail. Acad. Sci. USA 104: 19671-19678. 405
40 Scheres, S.H.W., Gao, H., Valle, M., Herman, G.T., Eggermont, P.P.B, Frank, J., and Carazo, J.-M. (2007). Disentangling conformational states of macromolecules in 3D-EM through likelihood optimization. Nat. Methods 4: 27-29. 413
41 Agirrezabala, X., Lei, J., Brunelle, J.L., Ortiz-Meoz, R.F., Green, R., and Frank, J. (2008). Visualization of the hybrid state of tRNA binding promoted by spontaneous ratcheting of the ribosome. Mol. Cell 32: 190-197. 416
42 LeBarron, J., Grassucci, R.A., Shaikh, T.R., Baxter, W.T., Sengupta, J., and Frank, J. (2008). Exploration of parameters in cryo-EM leading to an improved density map of the E. coli ribosome. J. Struct. Biol. 164: 24-32. 424
43 Trabuco, L.G., Villa, E., Mitra, K., Frank, J, and Schulten, K. (2008). Flexible fitting of atomic structures into electron microscopy maps using molecular dynamics. Structure 16: 673-683. 433
44 Villa, E., Sengupta, J., Trabuco, L.G., LeBarron, J., Baxter, W.T., Shaikh, T.R., Grassucci, R.A., Nissen, P., Ehrenberg, M., Schulten, K., and Frank, J. (2009). Ribosome-induced changes in elongation factor Tu conformation control GTP hydrolysis. Proc. Natl. Acad. Sci. USA 106: 1063-1068. 444
45 Agirrezabala, X., Liao, H.Y., Schreiner, E., Fu, J., Ortiz-Meoz, R.F, Schulten, K., Green, R., and Frank, J. (2012). Structural characterization of mRNA-tRNA translocation intermediates. Proc. Natl. Acad. Sci. USA 109: 6094-6099. 450
46 Hashem, Y., des Georges, A., Fu, J., Buss, S.N., Jossinet, F., Jobe, A., Zhang, Q., Liao, H.Y., Grassucci, R.A., Bajaj, C., Westhof, E., Madison-Antenucci, S., and Frank, J. (2013). High-resolution cryo-electron microscopy structure of the Trypanosoma brucei ribosome. Nature 494: 385-389. 456
47 Dashti, A., Schwander, P., Langlois, R., Fung, R., Li, W., Hosseinizadeh, A., Liao, H.Y., Pallesen, J., Sharma, G., Stupina, V.A., Simon, A.E., Dinman, J.D., Frank, J., and Qurmazd, A. (2014). Trajectories of the ribosome as a Brownian nanomachine. Proc. Natl. Acad. Sci. USA 111: 17492-17497. 463
48 Kinz-Thompson, C.D., Sharma, A.K., Frank, J., Gonzalez, R.L., and Chowdhury, D. (2015). Quantitative connection between ensemble thermodynamics and single-molecule kinetics: a case study using cryogenic electron microscopy and single-molecule fluorescence resonance energy transfer investigations of the ribosome. J. Phys. Chem. B 119: 10888-10901. 476
49 Li, W., Liu, Z., Koripella, R.K., Langlois, R., Sanyal, S., and Frank, J. (2015). Activation of GTP hydrolysis in mRNA-tRNA translocation by elongation factor G. Science Adv. 1: el500169. 490
50 des Georges, A., Clarke, O.B., Zalk, R., Yuan, Q., Condon, K.J., Grassucci, R.A., Hendrickson, W.A., Marks, A.R., and Frank, J. (2016). Structural basis for gating and activation of RyR1. Cell 167: 145-157. 497
51 Fu, Z., Kaledhonkar, S., Borg, A., Sun, M., Chen, B., Grassucci, R.A., Ehrenberg, M., and Frank, J. (2016). Key intermediates in ribosome recycling visualized by time-resolved cryoelectron microscopy. Structure 24:2092-2101. 516
52 Liu, Z., Gutierrez-Vargas, C., Wei, J., Grassucci, R.A., Ramesh, M., Espina, N., Sun, M., Tutuncuoglu, B., Madison-Antenucci, S., Woolford, J.L., Tong, L., and Frank, J. (2016). Structure and assembly model for the Trypanosoma cruzi 60S ribosomal subunit. Proc. Natl. Acad. Sci. USA 113: 12174-12179. 526
53 Maji, S., Shahoei, R., Schulten, K., and Frank, J. (2017). Quantitative characterization of domain motions in molecular machines. J. Phys. Chem. B 121: 3747-3756. 532
54 Twomey, E.C., Yelshanskaya, M.V., Grassucci, R.A., Frank, J., and Sobolevsky, A.I. (2017). Channel opening and gating mechanism in AMPA-subtype glutamate receptors. Nature 549: 60-65. 542
Corpus Acknowledgments 559
