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Workshops

Ribosome-associated protein folding: Translation, auxiliary factors, and translocation

May 29, 2012 to May 31, 2012
Location : CECAM-HQ-EPFL, Lausanne, Switzerland
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Organisers

  • Ed O'Brien (Pennsylvania State University, USA)
  • Michele Vendruscolo (University of Cambridge, United Kingdom)
  • Adrian Elcock (University of Iowa, Iowa City, USA)

Supports

   CECAM

Description

For the past several decades theoretical and experimental studies on protein folding have primarily focused on the behaviour of isolated proteins at equilibrium [1,2]. The interest in understanding the links between this fundamental problem and the function of proteins in living organisms, coupled with a series of major technical advances, has shifted the focus in this field to protein folding in vivo [3]. Understanding protein behaviour in this context presents novel computational and experimental challenges, but it also provides an opportunity to understand folding in its natural environment.

To understand protein folding in the cell the place to start is at the ribosome. The ribosome molecular machinery, which is present and highly conserved in all organisms [4], synthesizes proteins in a time-dependent, irreversible manner [5]. During their synthesis, nascent proteins have the opportunity to fold [6].  Therefore, understanding nascent protein folding is crucial to moving the entire in vivo folding field forward.  This is no easy task as the ribosome is a nexus for coordinating many molecular actors both spatially and temporally. These include mRNA and tRNA molecules whose properties can affect the rate of synthesis [7], chaperone and enzyme molecules that interact with the nascent chain as it emerges from the ribosome exit tunnel [8], and biological pores, such as the Sec translocon, that cotranslationally translocate the nascent chain through membranes [9]. Thus, translation, auxiliary factors and translocation are central features of ribosome-associated protein folding.

Understanding each of these facets has been an area of cutting edge research addressing fundamental biology questions. Experiments utilizing single molecule techniques [10], cryo-EM [9], deep sequencing [11] and a variety of other methods [12-16] have generated a wealth of data that can inform both theory and simulation and thereby provide fundamental insights into the physical principles of nascent protein folding [17]. Concurrently, theory and simulation methods are also being developed to model the length and time scales of such large biological systems [18-24]. At this crucial juncture, with advances being made on many fronts, it is important to bring together theoreticians and experimentalists to map out how these communities can move the in vivo protein folding field forward.

We will bring together the leading experts from both communities to discuss key challenges and important questions that could potentially be addressed through combined theoretical, computational and experimental effort. In this way we hope to motivate these communities to pursue research projects that would enrich each other, and offer the opportunity for deeper insights into ribosome-associated protein folding than may be possible otherwise.

This workshop will be limited to 40 participants and will involve both talks and a poster session. Those interested in attending should apply as soon as possible. Notification of acceptance will be given on a rolling basis.

Please email your application directly to eo264@cam.ac.uk, and list your interests in this area, your recent publications related to this topic, and whether you would like to give a talk or present a poster. If applying to give a talk, please provide a brief summary of what you will present. If you are a post-doc please also list the research group you are in. Incomplete applications will not be given consideration.

References

[1] J. D. Bryngelson, J. N. Onuchic, N. D. Socci, and P. G. Wolynes. Funnels, pathways, and the
energy landscape of protein-folding - A synthesis. Prot. Struc. Func. Gene., 21(3):167-195, 1995.
[2] D. Thirumalai, E. P. O'Brien, G. Morrison, and C. B. Hyeon. Theoretical perspectives on protein folding. Annu. Rev. Biophys., 39:159-183, 2010.
[3] S. Ebbinghaus, A. Dhar, J. D. McDonald, and M. Gruebele. Protein folding stability and dynamics imaged in a single cell. Nat. Meth., 7:319-323, 2010.
[4] J. A. Mears, J. J. Conne, S. M. Stagg, R. R. Gutell, R. K. Agrawal, and S. C. Harvey. Modeling a minimal ribosome based on comparative sequence analysis. J. Molec. Biol., 321(2):215-234, 2002.
[5] C. E. Aitken, A. Petrov, and J. D. Puglisi. Single ribosome dynamics and the mechanism of translation. Annu. Rev. Biophys., 39:491-513, 2010.
[6] K. G. Ugrinov and P. L. Clark. Cotranslational folding increases GFP folding yield. Biophys. J., 98(7):1312-1320, 2010.
[7] A. Czech, I. Fedyunin, G. Zhang, and Z. Ignatova. Silent mutations in sight: co-variations in tRNA abundance as a key to unravel consequences of silent mutations. Molec. Biosys., 6(10):1767-1772, 2010.
[8] G. Kramer, D. Boehringer, N. Ban, and B. Bukau. The ribosome as a platform for cotranslational processing, folding and targeting of newly synthesized proteins. Nat. Struc. Molec. Biol., 16(6):589-597, 2009.
[9] J. Frauenfeld, J. Gumbart, E. O. van der Sluis, and R. Beckmann. Cryo-em structure of the ribosome-SecY complex in the membrane environment. Nat. Struc. Molec. Biol., 18(5):614-627, 2011.
[10] C. E. Aitken and J. D. Puglisi. Following the intersubunit conformation of the ribosome during translation in real time. Nat. Struc. Molec. Biol., 17(7):793-800, 2010.
[11] N. T. Ingolia, S. Ghaemmaghami, and J. R. S. Newman and. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science, 324(5924):218-223, 2009.
[12] A. Rutowska, M. P. Mayer, A. Hoffmann, and B. Bukau. Dynamics of trigger factor interaction with translating ribosomes. J. Biol. Chem., 283(7):4124-4132, 2008.
[13] S. T. D. Hsu, L. D. Cabrita, P. Fucini, J. Christodoulou, and C. M. Dobson. Probing side-chain dynamics of a ribosome-bound nascent chain using methyl NMR spectroscopy. J. Amer. Chem. Soc., 131(24):8366-8367, 2009.
[14] G. Zhang, M. Hubalewska, and Z. Ignatova. Transient ribosomal attenuation coordinates protein synthesis and co-translational folding. Nat. Struc. Molec. Biol., 16(3):274-280, 2009.
[15] C. M. Kaiser, H. C. Chang, and V. R. Agashe. Real-time observation of trigger factor function on translating ribosomes. Nature, 444(7118):455-460, 2006.
[16] R. Maier, C. Scholz, and F. X. Schmid. Dynamic association of trigger factor with protein substrates. J. Molec. Biol., 314(5):1181-1190, 2001.
[17] E. P. O'Brien, J. Christodoulou, M. Vendruscolo, and C. M. Dobson. New scenarios of protein folding can occur on the ribosome. J. Amer. Chem. Soc., 133(3):513-526, 2011.
[18] E. P. O'Brien, S. T. D. Hsu, J. Christodoulou, M. Vendruscolo, and C. M. Dobson. Transient tertiary structure formation within the ribosome exit port. J. Amer. Chem. Soc., 132(47):16928-16937, 2010.
[19] M. W. Sneddon, J. R. Faeder, and T. Emonet. Efficient modeling, simulation and coarse-graining of biological complexity with NFsim. Nat. Meth., 8:177-183, 2011.
[20] N. Skjondal-Bar and D. R. Morris. Dynamic model of the process of protein synthesis in eukaryotic cells. Bull. Math. Biol., 69(1):361-393, 2007.
[21] K. Y. Sanbonmatsu and C. S. Tung. High performance computing in biology: Multimillion atom simulations of nanoscale systems. J. Struc. Biol., 157(3):470-480, 2007.
[22] J. Gumbart, C. Chipot, and K. Schulten. Free-energy cost for translocon-assisted insertion of membrane proteins. Proc. Natl. Acad. Sci., 108(9):3596-3601, 2011.
[23] A. H. Elcock. Molecular simulations of cotranslational protein folding: Fragment stabilities, folding cooperativity, and trapping in the ribosome. PLOS Comp. Biol., 2:824-841, 2006.
[24] P. C. Whitford, P. Geggier, R. B. Altman, S. C. Blanchard, and J. N. Onuchic. Accommodation of aminoacyl-tRNA into the ribosome involves reversible excursions along multiple pathways. RNA, 16(6):1196-1204, 2010.