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Work done by researchers
at the "Laboratoire Structure des Macromolécules Biologiques
et Mécanisme de Reconnaissance" (Laboratory of Biological
Macromolecule Structure and Recognition Mechanisms, CNRS – Strasbourg,
France) has made it possible for us to learn more about the mechanisms
involved in protein translation. It reveals a possible scenario of evolution
mechanisms leading to enzymes that are essential to the expression of
the genetic code. This research opens new prospects in the area of bioengineering
of the genetic code.
The 20 aminoacyl-tRNA synthetases (or tRNA synthetases, one for each amino
acid) are the enzymes responsible for binding amino acids to transfer
RNA (or tRNA), "adaptive" molecules that translate genetic information
coding for messenger RNA (resulting themselves from the transcription
of DNA). These reactions, known as aminoacylation, must be highly specific:
a binding error will lead to the incorrect incorporation of an amino acid
into the proteins. As a result, these enzymes are responsible for the
accurate expression of genetic information.
tRNA synthetases and tRNA are ancient proteins that were universally adopted
by all living organisms. It is believed that the two domains (one containing
the amino acid attachment site and the other containing the anticodon*
with the template reading head of the genetic code) making up the tRNA
appeared independently during the course of evolution and that the primitive
RNA synthetases existed in more simplified forms. But the stages that
made it possible for primitive tRNA synthetases to develop recognition
specificity of their tRNA substrates remain unknown.
Research into these enzymes has been conducted in France by the team of
Richard Giegé, CNRS research director, and in the United States
by Paul R. Schimmel of the Scripps Research Institute (San Diego, California).
By creating an artificial tRNA synthetase, these researchers have been
able to contribute convincing experimental arguments to support a possible
scenario that could have led to modern tRNA synthetases during the course
of evolution. The experimental "tRNA/tRNA synthetase" system
that made it possible to mimic evolution to achieve these results is the
one specific to the amino acid, alanine. This system is ingenious: as
a result of the way the tRNA synthetase specific to alanine (or tRNAAla)
recognizes its tRNA, it can be considered to be a primitive synthetase.
The artificial tRNAAla created by genetic engineering methods is a chimera
protein consisting of two structural domains, one providing recognition
and activation of alanine and the other responsible for the specificity
of RNA recognition and, therefore, the binding of alanine to this tRNA.
The experiment thus consisted of fusing these two domains. Several chimeras,
differentiated by the length of binding sequences between the two domains,
were created. Just as the researchers predicted, the chimeras were able
to bind the alanine to a microhelice that mimicked the acceptor arm of
the tRNAAla. They also demonstrated that these reactions were specific.
An important conclusion drawn from this research is that two protein domains
chosen by totally independent pathways (a natural pathway for the catalytic
domain and a non-natural pathway for the RNA recognition peptide) led
to the creation of a new biologically active protein (artificial tRNA
synthetase). According to the researchers, natural evolution followed
this logic and the primitive tRNA synthetases (as well as other proteins)
are the result of the fusion of independent and preexisting structural
domains. Another fascinating conclusion is that it is now possible to
remodel aminoacylation systems of tRNA by the fusion of constituent domains
and/or artificial domains of these proteins. This implies that it is possible
to remodel the genetic code.
(*) The anticodon
recognizes the codon, its complement on the messenger RNA.
Reference
"RNA recognition by designed peptide fusion creates 'artificial'
tRNA synthetase" by Frugier, Giegé and Schimmel, published
in the Proceedings of the National Academy of Sciences of the United
States, June 24, 2003 PNAS, vol. 100, pp. 7471-7475.
Researcher
contact:
Richard Giegé
Laboratoire Structure des Macromolécules Biologiques et Mécanisme
de Reconnaissance
Tel: +33 3 88 41 70 56/58
e-mail: R.Giege@ibmc.u-strasbg.fr
Press contact
:
Muriel Ilous
Tel : +33 1 44 96 43 09
e-mail : muriel.ilous@cnrs-dir.fr
Life Sciences
Department contact:
Françoise Tristani
Tel: +33 1 44 96 40 26
E-mail: francoise.tristani@cnrs-dir.fr
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