December 28, 2006 | David F. Coppedge

Cell Zippers, Linemen and Editors Put on a Show

The golden age of cell biology continues.  Scientists keep unlocking the secrets of cellular machinery with newer and better techniques.  With the curtain rising on a show we could not previously imagine, played out on a stage so small it took centuries of scientific work to even see it, biochemists are discovering amazing tricks that the little autonomous actors have been performing all along, right inside of us.

  1. Zip me up, road crew:  A press release on EurekAlert pointed to a new paper in Cell1 where researchers found a kind of monorail zipper.  The original paper by Kikkawa and Metlagel actually calls it a “molecular ‘zipper’ for microtubules.”  The EurekAlert article discusses “Roadworks on the motorways of the cell.”  Cellular highways are 3-D monorails that run in all directions and are constantly being formed and recycled.  Composed of protein units of tubulin, they first form into sheets that fold into a tube shape.  That’s where Mal3p comes in.  This little protein zips up the edges of the tube, forming a stable structure that would otherwise unravel easily.  The zipper even forms an alternate trackway for the molecular “trucks” that use the microtubules to deliver goods all over the cell (12/04/2003, 02/25/2003, 07/12/2004).
  2. Mr. Goodwrench, the inchworm:  DNA is tightly compacted in the cell, but needs to be unwound frequently for translation and duplication.  A family of machines called helicases unwind the double helix as part of the process.  Scientists wondered how the machine travels up and down the helix, and have now found that one particular helicase named UvrD both twists and jumps in a two-part power-stroke.  The authors of another paper in Cell2 describe this as a “wrench-and-inchworm” mechanism.  Each step, which traverses one DNA base at a time, requires two ATP fuel pellets.  See also 06/19/2003, 01/05/2006, bullet 9, and 10/27/2005, bullet 3; see 01/19/2005 about an RNA helicase.
  3. Not many typos get past this editor:  Life depends on 20 specialized translators that connect the DNA code to the protein code (see 09/16/2004 for historical background, and 06/09/2003 and its embedded links for conceptual background).  The awkwardly-named “aminoacyl-tRNA synthetases” (AARS for short) are highly specialized to connect the two codes correctly and edit out mistakes before they cause serious trouble.  A paper in PNAS3 discussed one of the ways the AARS for the amino acid phenylalanine works.  For jargon lovers, the model is: “the role of the editing site is to discriminate and properly position noncognate substrate for nucleophilic attack by water.”  To test the model, they tinkered with some of the pieces of the protein machine and watched the editing precision drop dramatically.  The precision of the active site is part of the “translational quality control,” they said (see 12/20/2003, 09/09/2002).
  4. Oxygen can be bad for your health:  We like to breathe in that oxygen, but in the wrong places it can be a poison.  Authors of another paper in PNAS4 found that “oxidized messenger RNA induces translation errors.”  They put the gene for the light-glowing protein luciferin into rabbits (imagine a glowing Bugs Bunny) in both oxidized and non-oxidized forms.  Although the oxidized translation machine stayed intact, the “translation fidelity was significantly reduced.”

How could such precision translation machinery evolve?  A paper in Structure,5 another Cell Press journal, bravely investigated the evolution of the genetic code (see 11/01/2002 for a previous attempt).  They understood the requirement for high fidelity: “This specificity is critical for the accuracy of the genetic code, which has to be maintained to the highest degree to prevent mistranslation, that is, incorporation of the wrong amino acids at specific codons.”  They tried to envision the transition from a hypothetical “RNA world” (07/11/2002) of miscellaneous floating ribozymes to the DNA-mRNA-tRNA-protein system now universally employed in all living things.  That’s no small order.  It requires a good imagination, as their introduction makes clear: 

Since the discovery of ribozymes and the development of the idea of life first emerging from an RNA world (Gilbert, 1986), biologists have struggled to imagine the logical progression of events that led to proteins.  At the same time, regardless of what the imagination can conjure, a connection to reality has to be made.  That, in turn, requires experiments to test specific hypotheses or to provide an opportunity for serendipitous findings.
    To go from RNA to proteins requires the genetic code—triplets of nucleotides representing single amino acids.  The modern code is an algorithm determined by aminoacylation reactions, whereby each of 20 amino acids is linked to its cognate tRNA that bears the anticodon triplet of the code.  The 20 aminoacyl tRNA synthetases (one for each amino acid) that catalyze these reactions are ancient proteins that were present in the last common ancestor of the tree of life (Carter, 1993 and Cusack, 1997).  As the eons passed, the tree split into the three great kingdoms—archaea, bacteria, and eukarya, which encompass all life forms.  Yet, the genetic code remained fixed, with the same 20 aminoacyl tRNA synthetases making the same connections between anticodon triplets and amino acids.  Thus, clues to the history of the transition from the RNA world to proteins might be imbedded in the tRNA synthetases themselves.

The best they could do was to suggest that a few of the aminoacyl-tRNA-synthetases hold hints of a prior RNA-ribozyme ancestry.  Three of them, for instance, perform the editing while gripped to the transfer RNA (tRNA), resembling a “ribonucleprotein” that might have been the successor to the initial ribozymes in the RNA soup.  The words might, may and perhaps were evident in their article, however.  These speculative words looked pretty stark next to the clear evidence of precision in the translating machinery.  The AARS for glutamine, for instance, is able to distinguish between four very similar-looking molecules and pick the right one.  A conformational change in the binding pocket kicks out the interlopers and makes sure the correct amino acid gets attached to the tRNA.  Their conclusion, therefore, seemed to make a giant leap of faith:

Thus, what is reported in this most recent work on GluRS—that a synthetase can use tRNA to direct a conformational change that perfects amino acid specificity, using in part a contact with the tRNA itself—may provide a general mechanism of tRNA-dependent amino acid specificity.  The much bigger implication is that perhaps this functional interaction is a picture or a “holdover” from an earlier era in the evolution of the genetic code.

1Kikkawa and Metlagel, “A molecular ‘zipper’ for microtubules,” Cell, Volume 127, Issue 7, 29 December 2006, Pages 1302-1304.
2Lee and Yang, “UvrD Helicase Unwinds DNA One Base Pair at a Time by a Two-Part Power Stroke,” Cell, Volume 127, Issue 7, 29 December 2006, Pages 1349-1360.
3Ling, Roy and Ibba, “Mechanism of tRNA-dependent editing in translational quality control,” Proceedings of the National Academy of Sciences USA, published online before print December 21, 2006, 10.1073/pnas.0606272104.
4Tanaka, Chock and Stadtman, “Oxidized messenger RNA induces translation errors,” Proceedings of the National Academy of Sciences USA, published online before print December 26, 2006, 10.1073/pnas.0609737104.
5Schimmel and Yang, “Perfecting the Genetic Code with an RNP Complex,” Structure, Volume 14, Issue 12, December 2006, Pages 1729-1730.

Hope you enjoyed another peek into cellular wonders.  We had to throw in an evolutionary tale just for the sheer contrast of seeing actual scientific investigation into observable machinery operating with high fidelity and quality control juxtaposed against the speculations of certain humans forced by their worldview to imagine that it just happened by chance.  You can see what they’re up against.  Shamelessly, they dove right into fantasyland, using their captive imaginations to portray impossibilities that they believe must have happened because, after all, we’re here, and no other approach than evolution is allowed in the dictatorship of King Charles.  Those of us with liberated minds no longer forced into contradictions can enjoy the non-fiction to the fullest.  We don’t know whether to sigh or chuckle at the fiction the slaves are forced to write.  The evolutionists are right on one point: “regardless of what the imagination can conjure, a connection to reality has to be made.”  We do hope they make it some day.

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