Scientist Uncovers Switch Controlling Protein Production
ScienceDaily (Dec. 22, 2010) — A scientist from the Florida campus of The Scripps Research Institute has discovered a molecular switch that controls the synthesis of ribosomes. Ribosomes are the large machineries inside all living cells that produce proteins, the basic working units of any cell. These new findings offer a novel target for potential treatments for a range of diseases, including cancer.
The study is published in the December 24, 2010 edition of theJournal of Molecular Biology.
The study identified the molecular switch, essentially formed by a small sequence of RNA, that controls a critical part of ribosome synthesis to allow for strict, albeit temporary, regulation of the process.
"These kinds of switches in RNA are thought to be slow acting," said Katrin Karbstein, an assistant professor in the Department of Cancer Biology at Scripps Florida who helped lead the study. "That suggests a point where we might intervene to modify the process -- then you could potentially shut down the pathway, because if you don't produce ribosomes, you cannot make proteins. Thus, cells can't grow. That would be a desirable outcome in cancer, for example."
This slowness may be there precisely so these regulatory points can be introduced for cells to downregulate growth when nutrition is scarce.
"Perhaps, nature has found a way to exploit RNA's Achilles' heel -- its propensity to form alternative structures that can lead to protein misfolding, which, in turn, can cause diseases ranging from Alzheimer's to diabetes," Karbstein said. "Nature might be using this to stall important biological processes and allow for quality control and regulation."
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Journal of Molecular Biology
Volume 405, Issue 1, 7 January 2011, Pages 3-17
An RNA Conformational Switch Regulates Pre-18S rRNA Cleavage
Allison C. Lamanna1, 1 and Katrin Karbstein1, 2, ,
1 Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor, MI 48109-1055, USA
2 Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA
Received 19 August 2010;
revised 27 September 2010;
accepted 29 September 2010.
Edited by D. E. Draper.
Available online 8 October 2010.
Abstract
To produce mature ribosomal RNAs (rRNAs), polycistronic rRNA transcripts are cleaved in an ordered series of events. We have uncovered the molecular basis for the ordering of two essential cleavage steps at the 3′-end of 18S rRNA. Using in vitro and in vivo structure probing, RNA binding and cleavage experiments, and yeast genetics, we demonstrate that a conserved RNA sequence in the spacer region between the 18S and 5.8S rRNAs base-pairs with the decoding site of 18S rRNA in early assembly intermediates. Nucleolar cleavage at site A2 excises this sequence element, leading to a conformational switch in pre-18S rRNA, by which the ribosomal decoding site is formed. This conformational switch positions the nuclease Nob1 for cytoplasmic cleavage at the 3′-end of 18S rRNA and is required for the final maturation step of 18S rRNA in vivo and in vitro. More generally, our data show that the intrinsic ability of RNA to form stable structural switches is exploited to order and regulate RNA-dependent biological processes.
Graphic Abstract
Research Highlights
► Cleavage at site A2 leads to a conformational switch in pre-18S rRNA. ► The decoding site is not formed in the early structure. ► Nob1 binds both structures but cleaves only the mature structure. ► Stabilizing the early structure delays Nob1-dependent cleavage in vivo. ► The switch orders cleavages at sites A2 and D.
Keywords: ribosome assembly; RNA conformational switch; RNA cleavage; RNP assembly
Abbreviations: rRNA, ribosomal RNA; H44, helix 44; ITS1, internal transcribed spacer 1
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