Predicting RNA Structure and Function. Nobel prize 1989 Nobel prize 2009 Ribozyme Ribosome

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  • Slide 1
  • Predicting RNA Structure and Function
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  • Nobel prize 1989 Nobel prize 2009 Ribozyme Ribosome
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  • RNA has many biological functions Enzymatic reaction (protein synthesis) Control of mRNA stability (UTR) Control of splicing (snRNP) Control of translation (microRNA) The function of the RNA molecule depends on its folded structure
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  • Protein structuresRNA structures Total 65000Total 700
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  • RNA Structural levels tRNA Secondary Structure Tertiary Structure
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  • RNA Secondary Structure U U C G U A A U G C 5 3 5 G A U C U U G A U C 3 STEM LOOP The RNA molecule folds on itself. The base pairing is as follows: G C A U G U hydrogen bond.
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  • RNA Secondary structure Short Range Interactions G G A U U G C C G G A U A A U G C A G C U U INTERNAL LOOP HAIRPIN LOOP BULGE STEM DANGLING ENDS 53
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  • The function of the RNA molecule depends on its folded structure Example: mRNA structure involved in control of Iron levels G U A G C N N N C N N 53 conserved Iron Responsive Element IRE Recognized by IRP1, IRP2
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  • IRP1/2 5 3 F mRNA 5 3 TR mRNA IRP1/2 F: Ferritin = iron storage TR: Transferin receptor = iron uptake IRE Low Iron IRE-IRP inhibits translation of ferritin IRE-IRP Inhibition of degradation of TR High Iron IRE-IRP off -> ferritin translated Transferin receptor degradated
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  • Predicting RNA secondary Structure Most common approach: Search for a RNA structure with a Minimal Free Energy (MFE) Fold, Mfold Zucker & Stiegler (1981) Nuc. Acids Res. 9:133-148 Zucker (1989) Science 244:48-52 RNAfold Vienna RNA secondary structure server Hofacker (2003) Nuc. Acids Res. 31:3429-3431
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  • Free energy model Free energy of a structure is the sum of all interactions energies Each interaction energy can be calculated thermodynamicly Free Energy(E) = E(CG)+E(CG)+..
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  • Why is MFE secondary structure prediction hard? MFE structure can be found by calculating free energy of all possible structures BUT the number of potential structures grows exponentially with the number, n, of bases
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  • RNA folding with Dynamic programming (Zucker and Steigler) W(i,j): MFE structure of substrand from i to j ij W(i,j)
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  • RNA folding with dynamic programming Assume a function W(i,j) which is the MFE for the sequence starting at i and ending at j (i