From the Department of Molecular Biology and Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037
The genetic code is based on the specific
aminoacylation of transfer RNAs (tRNAs) by aminoacyl-tRNA synthetases
(aaRS)1 (1, 2). This reaction
links anticodon triplets in tRNAs with specific amino acids. The
specificity of the reaction is governed by tRNA identity elements that
are recognized by the aminoacylating enzymes (2). The universal
distribution and conservation of tRNAs and aaRS imply that they
preceded the origin of the three kingdoms of life, Bacteria, Archae,
and Eucarya (3-5). Significantly, nucleotide determinants other than
the anticodon triplets are important for aminoacylation efficiency and
specificity (6, 7). It is these nucleotides (making up an operational RNA code) that are now seen as important for maintaining a universal genetic code.
Typically, aminoacylation occurs in two steps.
INTRODUCTION
TOP
INTRODUCTION
Background
The Minihelix and an...
Barriers to Cross-domain...
A Variation That Suggests...
An Example Where Identity...
Subtle Variations in...
Operational RNA Code in...
REFERENCES
Background
TOP
INTRODUCTION
Background
The Minihelix and an...
Barriers to Cross-domain...
A Variation That Suggests...
An Example Where Identity...
Subtle Variations in...
Operational RNA Code in...
REFERENCES
First, the enzyme (E) condenses its cognate amino acid
(AA) with ATP to form a tightly bound aminoacyl adenylate (AA-AMP) with
the release of pyrophosphate (PPi). The aminoacyl group is then transferred to the 3'-end of tRNA to give aminoacyl-tRNA (AA-tRNA)
and release of AMP. In this way, a specific nucleotide triplet
(anticodon) in the tRNA is physically connected (through the tRNA
structure) with a particular amino acid.
Transfer RNAs are usually comprised of 76 nucleotides arranged into a
cloverleaf structure with four major arms. The acceptor stem is a helix
of 7 bp that ends on the 3'-side with the universal tetranucleotide
NCCA76, with the amino acid attachment site at A76. The
dihydrouridine-, TC-, and anticodon-stem-loop make up the other
three arms (Fig. 1). The four arms are
arranged in three dimensions into an L-shaped structure (8, 9), where
the acceptor and T
C stems stack together to make up a 12-bp hairpin
known as the minihelix (ending in the T
C loop) (10). At right
angles, the D- and anticodon stems fuse to give a 10-bp helix with the
D-loop at one end and the anticodon loop at the other. Thus, the
triplet of the code and its cognate amino acid are in distinct domains
at opposite ends of the tRNA structure (Fig. 1).
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The minihelix domain terminating in the CCA trinucleotide is found as a regulatory element for replication of specific RNA genomes (11, 12). In the ribosome, the anticodon-containing and the minihelix domain bind to distinct rRNAs (13). This observation raises the possibility that the minihelix and anticodon-containing domains had separate origins. That an ancient minihelix duplicated and gave rise to the anticodon-containing domain and genetic code has also been proposed (14).
In bacteria, there typically is one aaRS for each amino acid. In
eukaryotes, distinct nuclear encoded cytoplasmic and mitochondrial enzymes carry out aminoacylations in their respective cellular compartments. Broadly speaking, the enzymes are comprised of two major
domains. The historical, most ancient domain contains the catalytic
site with determinants for binding the minihelix portion of the tRNA.
These catalytic domains are limited to two folds that define two
families known as classes I and II (15-19). (With rare exceptions,
each class contains enzymes specific for 10 different amino acids.)
Most of the structural evolution that gave rise to the two classes of
synthetases took place before the first split of the universal tree of
life based on analyses of 16 S RNA sequences (4, 5, 20). The
synthetases also have a second major domain that, in many instances,
interacts with the anticodon. The idiosyncratic structures of these
domains, even for enzymes within the same class, suggest that the
second domain was added later in evolution.
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The Minihelix and an Operational RNA Code for Amino Acids |
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An obvious way for an aaRS to relate a specific amino acid to a
nucleotide triplet is through direct recognition of the tRNA anticodon. However, the anticodon is not used as the principal determinant for aminoacylation by alanyl-, seryl-, or leucyl-tRNA synthetases (1). For example, bacterial and eukaryote cytoplasmic alanyl-tRNA synthetase throughout evolution rely on a specific G3:U70
base pair in the acceptor stem to define the identity of tRNAAla (21-25) (Fig. 2). No
physical contact is made by the enzyme with the anticodon (26). As a
consequence, a minihelix or even smaller helices (e.g.
microhelices of 7 bp) that contain a G3:U70 base pair are robust
substrates for aminoacylation by bacterial, yeast, and human enzymes
(10, 24, 25). Variants of these substrates with natural and non-natural
base analogs have been useful for evaluating energetic contributions of
the G3:U70 base pair (6, 27-29).
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These observations are mirrored by numerous examples of tRNA
synthetases that charge microhelices based on the sequences of the
acceptor stems of their cognate tRNAs (6, 7, 10, 30-44). Thus, despite
synthetase contacts with the anticodon (45), the acceptor stem often
contains determinants sufficient for specific aminoacylations. The
sequences/structures in RNA oligonucleotides that mimic the acceptor
stem and confer specific aminoacylations constitute an operational RNA
code for amino acids (46) (also referred to as the "second genetic
code" (47, 48)). These determinants typically are comprised of 1-3
bp and the N73 "discriminator" base. The operational RNA code may
have predated the genetic code and according to some analyses was the
progenitor of the genetic code (6, 48-52).
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Barriers to Cross-domain Aminoacylations and Their Manipulation |
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The tyrosine and glycine systems illustrate how the position of
acceptor stem determinants for aminoacylation, but not the determinants
themselves, have been conserved (1, 2). For example, eubacterial TyrRS
do not aminoacylate eukaryotic cytoplasmic tRNATyr (53).
Conversely, eubacterial tRNATyr cannot be aminoacylated by
eukaryotic TyrRS. This domain specificity correlates with the change of
the conventional G1:C72 base pair found in most tRNAs to C1:G72 in
eukaryotic and archaeal tRNATyr
sequences.2 The 1:72 base
pair was demonstrated to be important for aminoacylation of
microhelices or tRNAs based on sequences of tyrosine acceptors in
Bacillus stearothermophilus (55), the eukaryote pathogen Pneumocystis carinii (56), the yeast Saccharomyces
cerevisiae (56), and humans (57). Indeed, changing G1:C72 to
C1:G72 is sufficient to reverse the cross-domain specificity, that is
to enable a synthetase from bacteria to charge a substrate based on the
RNA sequence from an eukaryote or vice versa (Fig.
3) (57).
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Remarkably, these aminoacylation barriers could be overcome through the
generation of chimeric enzymes that contained a 39-amino acid fragment
of the eukaryotic enzyme within the context of the eubacterial TyrRS
(57). Conversely, incorporation of the bacterial peptide fragment into
the body of the human enzyme enabled the latter to charge the bacterial
substrate while losing its ability to charge the human RNA. These
experiments illustrate that the position of a determinant important for
aminoacylation was conserved and that coadaptations by the cognate
synthetase maintain specific recognition. A similar principle
presumably operates with glycyl-tRNA synthetases (Fig. 3) (58, 59).
Thus, acceptor-stem positions important for aminoacylation have been
conserved across phyla, and variations at these positions can account
for domain specificity of aminoacylation.
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A Variation That Suggests Relative Timing of Appearance of Synthetases and tRNAs |
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Unlike most species, the archaebacterium Methanococcus jannaschii does not have a gene coding for a class II lysyl-tRNA synthetase (60). Instead, aminoacylation of tRNALys is catalyzed by a class I enzyme (61). Phylogenetic analysis of the novel class I LysRS showed that its origin cannot be explained by a recent gene transfer event (62). Analysis of sequences of tRNALys from all phylogenetic domains showed that tRNALys does not divide into two groups that follow the distribution of its two different aminoacylating enzymes (62). The coherence of the tRNALys sequences implies that the identity of this tRNA was established independently (and probably before) the establishment of the two forms of LysRS (62). This situation is unlike the case of glutaminyl- and asparaginyl-tRNA synthetases. These two aaRS appeared later in evolution as result of duplications of genes for glutamyl- and aspartyl-tRNA synthetases, respectively, that were laterally transferred across the phylogenetic tree (63, 64).
Class I tRNA synthetases recognize the minor groove side of the
acceptor stem whereas class II enzymes approach tRNA from the major
groove side (18, 65-67). Many tRNALys contain an important
(for aminoacylation) G2:C71 and can be aminoacylated by both class I
and class II LysRS (68). This result implies that opposite sides (and
distinct atoms) of the same base pair are recognized by the two types
of enzymes. In contrast, tRNALys from the spirochete
Borrelia burgdorferi (an organism that has a class I LysRS)
contains a G:U base pair at position 2:71. This G:U base pair blocks
aminoacylation of tRNALys by class II Escherichia
coli LysRS (68). Thus, displacement of the class II LysRS by its
class I counterpart in spirochetes was possibly because of a subtle
variation in the operational RNA code for lysine that blocked
interaction with class II LysRS (68, 69) (Fig.
4). We suggest that the evolution of
pre-existing identity elements in ancestral tRNAs may have been one of
the main evolutionary pressures for selection of emerging forms of aminoacyl-tRNA synthetases.
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An Example Where Identity Element Variations Are Uncommon |
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In addition to the strong conservation of G3:U70 to mark a tRNA for aminoacylation with alanine (Fig. 2), aspartyl-tRNA synthetase (AspRS) has a widely conserved system for recognition of tRNAAsp through interactions with the anticodon triplet and the G73 discriminator base (1, 70). A phylogenetic tree derived with AspRS shows that its species distribution is highly coincident with the canonical tree of life (71). (PheRS, LeuRS, and GluRS are the only others to show the same coincidence (64).) Thus, although it might be expected that an enzyme that recognizes a set of universal identity elements would easily transfer between species, the population of genes coding for AspRS has not been subject to lateral gene transfers across different phyla.
We propose that the lack of documented examples of such transfers may be related to the ability of AspRS to recognize the related tRNAAsn in certain organisms. For example, in archaea, a canonical asparagine-tRNA synthetase is missing. The aminoacylation of tRNAAsn with asparagine is accomplished through an initial aspartylation of tRNAAsn catalyzed by AspRS. (This aspartylation is followed by a transamidation catalyzed by a separate enzyme (72).) Not surprisingly, archaeal tRNAAsn contains the important G73. To recognize tRNAAsn, archaeal AspRS has a modified recognition mechanism for the anticodon. In particular, it is insensitive to the base at position 36 (the only anticodon difference between tRNAAsn and tRNAAsp) (73).
Bacterial and eukaryotic organisms do not require this mechanism of generating Asn-tRNAAsn, because they utilize a canonical AsnRS that probably arose as a duplication of an ancient AspRS. The canonical distribution of AspRS may occur in part because archaeal organisms require an enzyme of loose tRNA specificity. Thus, these organisms cannot utilize a bacterial or eukaryotic AspRS that would not aminoacylate tRNAAsn.
Thermus thermophilus, an eubacterium that
contains a normal AsnRS and an archeal AspRS, represents the only
example (so far) of lateral transfer of an archaeal AspRS into another
kingdom. This situation could represent an isolated adaptation in
Thermus against asparagine starvation (71). In such
circumstances, Thermus would shift from the usual
aminoacylation of tRNAAsn by AsnRS to a more complex
pathway of charging tRNAAsn with aspartate using the
archaeal type AspRS and later transforming the tRNAAsp into
tRNAAsn via a transamidase reaction (71). Indeed, the
transamidase is found in T. thermophilus (74).
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Subtle Variations in Operational RNA Code May Be Essential to Maintain a Universal Genetic Code |
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At the time of emergence of the translational apparatus, the operational RNA code had the capacity to adapt to the problems of discrimination of increasingly large populations of RNA molecules. These populations extended beyond just tRNAs to cellular RNAs such as mRNAs that could potentially cross-bind and thereby inhibit a tRNA synthetase. Identity elements in tRNA acceptor stems mutated in different taxonomic groups, preventing cross-species aminoacylations of many different tRNAs. These aminoacylation barriers blocked genetic exchanges involving genes for tRNAs and their synthetases and were probably important to avoid disruption of the genetic code. In particular, if two distinct synthetases for the same amino acid are present (either via gene duplication or because of lateral gene transfer), then mutations can accumulate in one of them while the other is held fixed. It is understood that gross mischarging would be rapidly eliminated, but more subtle interactions with suppressor tRNAs or tRNAs containing infrequent codons could alter the amino acid or tRNA specificity and gradually introduce changes in the codon-amino acid relationships (75).
Disruption of the universal genetic code has happened in rare
instances, but its overall conservation points to the existence of
strong selection pressures against its variation. In this context, the
operational RNA code for aminoacylation of tRNA molecules would act as
a strong deterrent against contamination of the code through
nonspecific charging. This requirement for tight tRNA recognition might
explain why most tRNA synthetases in bacteria and archaea are encoded
by single copy genes. With single copy genes, the opportunity for
contamination of the genetic code is greatly restricted. The situation
in eukaryotes is essentially the same. A separate, distinct gene is
designated for a synthetase in each cell compartment, the cytoplasm and mitochondria.
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Operational RNA Code in Relation to Emergence of Eukaryotic Cell |
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The combination of archaebacterial and eubacterial species gave rise to the eukaryotic cell and generated organelles like plastids and mitochondria (76). The physiologic fusion of these species had to include integration of their systems for aminoacylation. The evolutionary solution to the duplicated synthetase-tRNA systems could have been determined by the interplay between mutations in the synthetases (and acceptor stem elements) that were being merged (54, 64). Eventually, two compartments, mitochondria and cytoplasm, emerged that utilized the same genetic code.
For example, two genes for the same enzyme activity (cytoplasmic and mitochondrial) are encoded by the genomes of contemporary eukaryotes. The possibility for two versions of the same enzyme ending up in the same cellular compartment is consequently significant. Were a misplaced mitochondrial enzyme to recognize the same acceptor stem elements as its cytoplasmic counterpart, the presence of two synthetases in the cytoplasm (targeted to the same acceptor stem) gives opportunity to invade and alter the genetic code (see above). By having distinct recognition elements for the mitochondrial form, the likelihood of such an invasion is greatly diminished. This consideration may account in part for why acceptor stem elements for animal mitochondria show more differences from their cytoplasmic counterparts than is typically seen for the same elements compared across taxonomic domains. Thus, although throughout evolution the G3:U70 base pair marks a tRNA for aminoacylation with alanine (Fig. 2), G3:U70 is often not found in animal mitochondrial tRNAAla. (However, G3:U70 is commonly found in mitochondria of other eukaryotes.2) Analysis of identity elements for other animal mitochondrial tRNA sequences revealed that tRNAAla is not an isolated example.
The striking variations in animal mitochondrial tRNA identity elements may also be related in part to a decreased level of genome complexity. In general, the set of tRNA genes in animal mitochondrial genomes is largely reduced (E. coli contains 40 tRNA genes, and the human mitochondria contains 22). This reduction means that aaRS tRNA synthetases now have to discriminate among a smaller population of tRNA molecules. Perhaps, under these circumstances, the evolutionary pressure to maintain a given set of identity elements is reduced, because certain discrimination problems no longer exist.
In summary, the genetic code is seen as preserved throughout evolution
(across all taxonomic domains and in higher eukaryotes with their
separate cell compartments) as a consequence of adaptations in the
identity elements in tRNA acceptor stems that constitute an operational
RNA code. These adaptations are a necessary consequence of the need to
keep anticodon sequences fixed to have a universal code, on the one
hand, and on the other, the need to facilitate the expansion and
diversification of living organisms. This ancient RNA code, which may
have started with the sequence-specific aminoacylation of
minihelix-like precursors of tRNAs by ribozymes, has endured long after
the genetic code was established because it offered a defense against
invasions of the code arising from tRNA synthetases with amino
acid-anticodon assignments that differed from those of the universal
code. It also endured because of its capacity to respond to
increasingly large and diverse populations of RNAs and the problems of
discrimination that they presented.
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. This work was supported by Grant 23562 from the National Institutes of Health and by a fellowship from the National Foundation for Cancer Research.
To whom correspondence should be addressed: BCC-379, Scripps
Research Inst., 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel.:
858-784-8976; Fax: 858-784-8990; E-mail: schimmel@scripps.edu.
Published, JBC Papers in Press, January 12, 2001, DOI 10.1074/jbc.R000032200
2 M. Sprinzl, K. S. Vassilenko, J. Emmerich, and F. Bauer, unpublished data.
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ABBREVIATIONS |
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The abbreviations used are: aaRS, aminoacyl-tRNA synthetase(s); bp, base pair(s).
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