Abstract

The biological function of RNA is intimately related to its three-dimensional structure. The objectives of this proposal are to understand how the sequence and structure of an RNA determines its folding pathway and thermodynamic stability, and to elucidate how ribozymes fold during transcription, a mimic of in vivo folding behavior. The catalytic RNA component from bacterial ribonuclease P will be used throughout this proposal. The catalytic, C-domain of this ribozyme folds without kinetic traps, providing an ideal system for the analysis of tertiary RNA folding.
Aim I focuses on how the C-domain builds its structure over time, and identifies critical features of the limiting step. To explore the strategies employed by natural RNAs to modulate their stability, Aim 2 will identify the minimal number of sequence changes necessary to create a thermophilic ribozyme from its mesophilic homologue.
Aim 3 extends our investigation of the principles of ribozyme stability to another class of RNase P RNAs that have the same catalytic core, but different peripheral regions.
Aim 4 is to test whether species-specific pausing during transcriptional elongation is a mechanism for enhancing folding during transcription. This broad research program will deepen our understanding in how RNA folds into its tertiary structure and establish the fundamental principles of RNA folding.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057880-08
Application #
6931180
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Lewis, Catherine D
Project Start
1998-08-01
Project End
2007-05-29
Budget Start
2005-08-01
Budget End
2007-05-29
Support Year
8
Fiscal Year
2005
Total Cost
$256,945
Indirect Cost

  Institution

Name
University of Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637

  Publications

Parisien, Marc; Wang, Xiaoyun; Perdrizet 2nd, George et al. (2013) Discovering RNA-protein interactome by using chemical context profiling of the RNA-protein interface. Cell Rep 3:1703-13
Liu, Yufeng; Haddadian, Esmael; Sosnick, Tobin R et al. (2013) A novel implicit solvent model for simulating the molecular dynamics of RNA. Biophys J 105:1248-57
Parisien, Marc; Freed, Karl F; Sosnick, Tobin R (2012) On docking, scoring and assessing protein-DNA complexes in a rigid-body framework. PLoS One 7:e32647
Perdrizet 2nd, George A; Artsimovitch, Irina; Furman, Ran et al. (2012) Transcriptional pausing coordinates folding of the aptamer domain and the expression platform of a riboswitch. Proc Natl Acad Sci U S A 109:3323-8
Haddadian, Esmael J; Gong, Haipeng; Jha, Abhishek K et al. (2011) Automated real-space refinement of protein structures using a realistic backbone move set. Biophys J 101:899-909
Baird, Nathan J; Ludtke, Steven J; Khant, Htet et al. (2010) Discrete structure of an RNA folding intermediate revealed by cryo-electron microscopy. J Am Chem Soc 132:16352-3
Geslain, Renaud; Pan, Tao (2010) Functional analysis of human tRNA isodecoders. J Mol Biol 396:821-31
Baird, Nathan J; Gong, Haipeng; Zaheer, Syed S et al. (2010) Extended structures in RNA folding intermediates are due to nonnative interactions rather than electrostatic repulsion. J Mol Biol 397:1298-306
Gong, Haipeng; Freed, Karl F (2010) Electrostatic solvation energy for two oppositely charged ions in a solvated protein system: salt bridges can stabilize proteins. Biophys J 98:470-7
Pan, Tao; Sosnick, Tobin (2006) RNA folding during transcription. Annu Rev Biophys Biomol Struct 35:161-75

Showing the most recent 10 out of 24 publications