Downloaded from symposium.cshlp.org on May 17, 2016 - Published by Cold Spring Harbor Laboratory Press
Peptide-specific Ribosomes, Genomic Tags, and the
Origin of the Genetic Code
N. MAIZELS AND A.M. WEINER
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine,
New Haven, Connecticut 06510
Contemporary protein synthesis requires more than
100 components. The ribosome itself consists of two
large RNAs, one or two small RNAs, and over 50
polypeptides. In addition, active translation requires an
mRNA template, numerous initiation, elongation, and
termination factors, several dozen specifically charged
tRNAs, the cognate tRNA synthetases, and a continuing source of ATP and GTP. To reconstruct the origin
of protein synthesis, it is necessary to conceive of a
scenario in which one of these interdependent components had a role in the absence of the others. Most
previous models have focused on the emergence of the
ribosome and the genetic code, and have simply assumed the prior existence of tRNAs, tRNA synthetases, and suitable mRNAs.
We have suggested that tRNA-like structures first
evolved as tags at the 3' ends of RNA genomes to mark
these genomes for replication in the ancient RNA
world (Weiner and Maizels 1987). We showed that this
genomic tag model can account for the existence of a
population of relatively homogeneous tRNAs, as well
as for their specific aminoacylation via a series of reactions completely analogous to contemporary tRNA
charging. If this scenario is correct, the first tRNAs and
tRNA synthetases predate the other major components
of the translation apparatus. Early ribosomes then most
likely evolved to facilitate the use of this population of
charged tRNAs in polypeptide synthesis. In this paper,
we outline arguments for believing that a rudimentary
genetic code evolved before mRNA. This would imply
that the principal components of the translation apparatus evolved in this order: tRNAs, tRNA synthetases, the ribosome, the genetic code, and finally
mRNA.
Here we argue that the driving force for the evolution of protein synthesis was the ability of early ribosomes to synthesize useful proteins, which were not
random polypeptides but essentially homopolymers.
We revive the notion of the peptide-specific ribosome
(Brenner et al. 1961; Brenner 1962; Gros et al. 1961)
and propose that during a brief period in the early
evolution of protein synthesis, each ribosome did in
fact carry its own template. Base pairing between this
internal template and a region on the tRNA defined
both the location and sequence of the anticodon within
the tRNA structure, thereby establishing the rudiments
of the genetic code. Although a peptide-specific ribosome would not have been as versatile as a modern
template-dependent ribosome, it would have had two
striking virtues as a precursor of the modern proteinsynthesizing apparatus: Peptide-specific ribosomes provide a pathway for the evolution of a rudimentary
genetic code, as well as a plausible genetic origin for the
first external templates or mRNAs.
Spontaneous Peptide Bond Formation
Peptide bond formation requires a source of activated amino acids. Once a tRNA synthetase activity
had evolved, the earliest oligopeptides were probably
synthesized by spontaneous peptide bond formation
between activated aminoacyl-tRNAs. The first primitive ribosome would then have evolved to accelerate
peptide synthesis by positioning the charged tRNAs
adjacent to each other. In fact, in light of the many
unsuccessful attempts to isolate a ribosomal protein
with peptidyltransferase activity, the suspicion is beginning to emerge that modern ribosomes accelerate spontaneous peptide bond formation primarily by aligning
the charged tRNAs (Moore 1985; Moore; Noller et al.;
and Nomura et al.; all this volume). In addition, the
facility with which the translation apparatus catalyzes
formation of unnatural bonds such as esters, thioesters,
thioamides, and phosphinoamides further supports the
notion that the peptidyltransferase center does not participate directly in peptide bond formation. Its primary
functions are probably to align the reacting groups and
to promote general acid/base catalysis, deprotonating
the a-amino group of the aminoacyl-tRNA, and possibly protonating the carbonyl group of the peptidyltRNA (for review, see Spirin and Lim 1986).
We wish to emphasize here, as we have previously
(Weiner and Maizels 1987), that a primitive ribosome
with only two equivalent tRNA-binding sites need not
have been restricted to the synthesis of dipeptides.
After such a ribosome had catalyzed formation of the
first peptide bond, the discharged tRNA might dissociate and be replaced by another charged tRNA
before the newly made dipeptidyl-tRNA dissociated
from the ribosome. In this case, a second round of
peptide bond formation could produce a tripeptidyltRNA, and so forth. Eventually, spontaneous hydrolysis of the peptidyl-tRNA bond would release the
free polypeptide.
Early Ribosomes May Have Produced Homopolymers
The synthesis of random polypeptides is unlikely to
have been sufficiently useful to drive the evolution of
Cold Spring Harbor Symposia on Quantitative Biology, VolumeLII. 9 1987 Cold Spring Harbor Laboratory0-87969-054-2/87 $1.00
743
Downloaded from symposium.cshlp.org on May 17, 2016 - Published by Cold Spring Harbor Laboratory Press
744
MAIZELS AND WEINER
the protein-synthesizing apparatus. Instead, the first
useful oligopeptides were probably homopolymers containing amino acids with chemically similar side
chains--basic, hydrophobic, perhaps even acidic. We
therefore suggest that each stage in the early evolution
of protein synthesis was optimized for the synthesis of
homopolymers. Initially, such synthesis may have reflected the existence of only a single class of tRNA
synthetases, capable of charging tRNAs with amino
acids carrying only a single class of side chain. At this
stage, homopolymers would necessarily have been the
sole polypeptide products of both spontaneous and
ribosome-accelerated polymerization.
Basic amino acids may have participated most readily
in both tRNA charging and spontaneous peptide bond
formation, because the positively charged amino acid
side chains could form ionic bonds with the negatively
charged phosphate backbone of the RNAs (Weiner and
Maizels 1987). Also, the resulting basic peptides would
have been especially useful in an RNA world, because
they could increase both the rate and variety of RNAcatalyzed reactions by efficiently neutralizing the backbone charge. Thus, the first biologically synthesized
pol}cpeptides may have functioned much like the modern polyamines, spermine and spermidine.
In addition, interaction of basic (but not neutral)
polypeptides with a nucleic acid has been shown to
facilitate inclusion of the resulting nucleoprotein complex within a lipid vesicle, suggesting an important role
for basic polypeptides in early compartmentation (Jay
and Gilbert 1987). Compartmentation must have been
a very early event in evolution: A genome and its
products must have remained together as a unit, since
extensive mixing of molecular components would
otherwise preclude evolution by natural selection.
Variant tRNA Synthetases Posed Both a Danger
and a Challenge
Although at first there may have been only one kind
of tRNA synthetase and one kind of peptide-specific
ribosome, natural variation would inevitably have led
to the emergence of variant tRNA synthetases with
novel charging specificities, posing both a danger and a
challenge to the primitive protein-synthesizing apparatus. A ribosome that directed indiscriminate polymerization of several different amino acids would have
produced random polypeptides, conferring little, if
any, selective advantage. Thus, there was strong selective pressure for the emergence of new classes of peptide-specific ribosomes that could recognize the new
species of charged tRNA and polymerize them into
homopolymers.
The Early Evolution of the Genetic Code
As Crick first pointed out, nucleic acids are not
chemically suited to forming a three-dimensional template with cavities or pockets that can arrange specific
amino acids for polymerization (Crick 1957). Instead,
he postulated the existence of bifunctional "adapter
molecules" which could simultaneously or sequentially
recognize both a nucleic acid sequence and the specific
amino acid it encoded. The discovery of the role of
tRNA in protein synthesis dramatically confirmed the
adapter hypothesis and also suggested that the adapter
molecules recognize the mRNA template through base
pairing. Since molecular evolution tends to be conservative, this would imply that very early tRNAs also
recognized their template through base pairing.
The adapter hypothesis provided no clues about the
mechanism responsible for specific aminoacylation of
different primitive tRNAs. One possible explanation
was that each of the primitive amino acids may have
interacted chemically with its cognate anticodon (see
Hopfield 1978). In this view, it was chemistry that
dictated the primitive genetic code, and the code itself
was in some respects inevitable, given the available
nucleic acid bases and amino acids. However, experiments designed to demonstrate such an interaction (for
review, see Lacey and Mullins 1983) are not compelling.
In contrast, if the specificity of aminoacylation is
determined by the interaction of the tRNA synthetase
with its tRNA (Weiner and Maizels 1987), there will be
no chemical interaction between the amino acid and the
anticodon. The interaction of the synthetase with the
tRNA would determine the specificity of aminoacylation. A code that developed in this fashion would be
an historical accident: Any combination of bases could
have encoded a particular amino acid, and the broad
outlines of the code we know would have been fixed by
those codons that happened to be immortalized first.
The Role of the Anticodon Loop
We argued above that the synthesis of random polypeptides would not have been advantageous, and thus
that it was essential for primitive ribosomes to discriminate between charged tRNAs bearing different aminoacyl groups. How might this have occurred? One possibility is that the primitive ribosome recognized the
aminoacyl group of the charged tRNA. This would,
however, condemn the ribosome to be terminally peptide-specific. No such ribosome, even if it existed, could
have been a precursor of the modern ribosome. We
suggest instead that primitive ribosomes, like modern
ribosomes, interacted with the RNA component of the
various aminoacylated tRNAs.
We further suggest that the site of specific basepairing between the tRNA and the ribosome defined
the primitive anticodon. Although such a ribosome
could be viewed as template-independent, a better description would be that its template is internal. This
internal template would then function as a built-in
mRNA for protein synthesis.
The precursor of the anticodon loop itself may have
served some function independent of protein synthes i s - f o r example, recognition by the replicase, by
RNase P, or by another RNA enzyme--that required it
Downloaded from symposium.cshlp.org on May 17, 2016 - Published by Cold Spring Harbor Laboratory Press
P E P T I D E - S P E C I F I C RIBOSOMES
to be conserved in all species of the diversifying tRNA
population. Initially, the anticodon loop in each species
of tRNA may have been free to interact with its cognate peptide-specific ribosome in a different way. Thus,
one tRNA and its corresponding peptide-specific ribosome might have employed a provisional genetic code
using two contiguous base pairs, whereas other such
interactions used three or even four (perhaps noncontiguous) base pairs. As discussed below, the advent of
template translocation would have been required to
extinguish this polyglot code, and to establish a uniform
genetic code consisting of three contiguous bases.
Thermodynamics of the Primitive Codon/Anticodon
Interaction
We have argued that the frst ribosome consisted of
two tRNA-binding sites, and that additional interactions between the ribosome and the tRNA determined
the specificity of protein synthesis and the sequence of
the anticodon. But if the ribosome already had a general affinity for all tRNAs, how could an additional
base-pairing interaction with the provisional anticodon
allow the ribosome to distinguish between closely related species of tRNA?
The affinity of the tRNA for its binding site(s) on the
ribosome may have drawn on both a specific and a
nonspecific component. The nonspecific component
would represent interactions of the ribosome with
many sites on the tRNA other than the future anticodon, and the ribosome/anticodon interaction would
represent the specific binding component. For an analogy, consider the interaction between lac repressor and
lac operator. The overall dissociation constant for repressor bound to operator is an impressive 10 -13 M, but
more than half of this (10 -8 M) can be attributed to
nonspecific ionic interactions of repressor with the
D N A backbone. The specific component, which primarily reflects hydrogen bonding of the amino acid side
chains to the D N A bases, accounts for an increment of
only 10 -5 M (see Ptashne 1986). Thus, despite the high
affinity of repressor for nonspecific DNA, the incremental increase in affinity due to specific binding
allows repressor to distinguish its own unique site from
a million other possible sites on the Escherichia coli
chromosome. This analogy suggests that the incremental energy of base-pairing between the anticodon loop
of each particular tRNA species and a corresponding
built-in m R N A segment on the ribosome would have
been sufficient to maintain the peptide-specificity of
each species of ribosome.
Evolution of the Internal Template
Initially, each tRNA-binding site on the primitive
ribosome probably functioned independently, and the
frst internal template may have consisted of two noncontiguous RNA segments, one for each binding site.
What then was the driving force that brought the two
anticodon-binding sites together as a continuous inter-
745
nal template? We suggest that the clues are to be found
in the structure of the modern ribosome, where the
highly conserved 3' domain of 16S rRNA (for review,
see Van Knippenberg 1986) appears to participate in an
intricately stacked quaternary complex involving two
adjacent bound tRNAs and the mRNA.
Studies of allosteric interactions between aminoacylated tRNAs bound at the A and P sites (Nierhaus et al.
1986), as well as fluorescence transfer measurements
between wye base residues located 3' to the anticodon
(Fairclough and Cantor 1979), indicate that tRNAs in
the A and P sites contact the m R N A simultaneously on
the modern ribosome. Simultaneous contact is strictly
unnecessary for information transfer. Only the incoming aminoacyl-tRNA needs to decode the mRNA; the
tRNA bearing the nascent chain has already performed
its decoding function. We would therefore interpret
these interactions as a molecular fossil, revealing the
design of the ancient ribosome rather than the requirements of contemporary protein synthesis.
Not only do both tRNAs appear to contact the
m R N A simultaneously, but C1400 of 16S r R N A can be
photocrosslinked to the wobble base of tRNA bound at
the P site (for review, see Ofengand et al. 1986), and
the wye base of tRNA at the A site can be photocrosslinked to the 5' base of the corresponding codon in the
m R N A (Steiner et al. 1984). In order to accommodate
the bulk of two adjacent anticodon stems, the m R N A
between the two codons must be kinked (Rich 1974;
Sundaralingam et al. 1975). In the modern ribosome, a
kinked template would serve to bring the two 3' acceptor ends of the stiff, L-shaped tRNAs into proximity, so
that peptide bond formation is rapid, once the fourR N A interaction has occurred.
We therefore suggest that the intricate stacking interactions on the modern ribosome may be a molecular
fossil of the primitive ribosome, where such interactions could have promoted cooperative binding of
tRNAs. The potential for such cooperative binding
would favor realignment of the tRNA-binding sites
(and perhaps even some reshaping of the tRNAs themselves) to generate adjacent anticodon-binding sites on
a continuous internal template,
In principle, each new species of peptide-specific
ribosome could have arisen de novo. However, the first
ribosome to use stacking interactions between contiguous codon/anticodon triplets to achieve cooperative
tRNA binding would have had a powerful selective
advantage. We suggest that this particular ribosome
was the precursor of the modern ribosome. Natural
variation in its internal template would have generated
new peptide-specific ribosomes, which in turn recognized new species of tRNA through specific base-pairing interactions with the anticodon loop.
Figure 1 diagrams a scheme for the evolution of a
peptide-specific ribosome. The scheme begins with an
R N A molecule that has a tRNA-binding site. The
genomic tag model suggests that such binding sites
characterized all early replicases, so a variant replicase
may well have been the molecular starting point for the
Downloaded from symposium.cshlp.org on May 17, 2016 - Published by Cold Spring Harbor Laboratory Press
746
MAIZELS AND W E I N E R
RNA moleculewith
binding site for
lysyl~tRNAcan form
base pairs with
CCAoH and UUU
anticodon; positively
charged amino group
of lysine side chain
would interact with a
negatively charged
phosphate group
at binding site
(not shown)
U
!~! ~ i ~ ~
I
~,
~'~'~
C,~
C \~ \
~'~ ~
C-CHR-NH--C-CHR-NH
z
~
~ .
~
. ,, " " - ~ ' ~ - ' ~ L
/
C~Gu Gu ~
~]
C_G
G
~ I/
UUU(
[
I
~
AAA AAA.
cation of tRNA
bindingsite by
replication en'or
or RNA recombination
9. . , " " - ' ~ . " ' ~
)
Gu G~ ~
~ ]
/
~
----'/
~
r
Nascentpeptidyl~tRNAtranslocatesfrom
A site to P site by dissociation
and reassociationwith protoribosome;
Iisyl~tRNAmay bindto protorilx~some
~
/~C CHRNH-\CII CHR-NH2
/
6
,o"
\
] ..~---,,,.,~...-.--~. ~
A U A U"~ ~, J
C G rCnG ~ ~/
AAA AAA-~
(
positively
charged aminoacyl
group, dissociates
from protoribosome
.
x.....~ '.
Protoribosomewith
two tRNA binding
sites and built-in
Discharged tRNA,
now lackinga
iilIH/UUU /"
| I
i~iA l iA ;~-(I /I
- : ~- " ~ . ~ / ) /
" "z \
~ I~
~
"
New lysyl~tRNA
can react with bound
dilysyl~tRNAto yield
trilysyl~tRNA,etc.
Dissociation of
~176
followed by hydrolysis
of activated
aminoacyl bond,
yields oligolysine
Further
.~ evolution
o//~-CHR-:?~-CHR-NHz~
~
GU
C
C .G C G
uuu/uuu /
! J i A A ~AAA - ~ A
followed by
I
I
|/
I
. . . . .
Binding of two
spontaneous
formation
peptide bond
NHi~--CHR-NHz
cAGU
CG CG
|
|/
meNA
UUU(UUU /
I
|
3'--AAAAAAAAA ~A AAAAAAAA~_A/z~j
9\
through mutation and
replaced with separate
mRNA template
~jIT~-0
Figure 1. A model for the evolution of a peptide-specific protoribosome into a modern template-dependent ribosome. Since the
first tRNA synthetases are likely to have been specific for basic amino acids, a lysine-specificprotoribosome is illustrated here. For
clarity, the tRNAs are cartooned as hexanucleotides.
evolution of the ribosome. The scheme outlines the
development of a relatively sophisticated protoribosome, which carries an internal template and can bind
and position two aminoacylated tRNAs for spontaneous peptide bond formation. For simplicity, tRNAs
are cartooned as hexanucleotides; all the evidence implies that early tRNAs were in fact much more complex.
tRNA Translocates but the Internal Template
Does Not
In the absence of a mechanism for tRNA translocation, a single round of peptide bond formation on the
primitive ribosome would usually be followed by release of both the dipeptidyl and the uncharged tRNAs.
Synthesis of proteins larger than dipeptides would require successive cycles of association and dissociation,
and thus be inefficient.
We suggest that a simple mechanism for tRNA translocation arose early. The two equivalent tRNA-binding
sites on the primitive ribosome might have become
nonequivalent, so that the affinity of the peptidyl site
(P site) but not the aminoacyl site (A site) was higher
for aminoacyl-tRNA than for uncharged tRNA. Following the first round of peptide bond formation, the
association constants would favor release of the uncharged tRNA from the P site, and movement of the
peptidyl-tRNA from the A site to the P site. Synthesis
of longer and longer polypeptides could then occur in
this stepwise fashion, as diagrammed in Figure 1.
Previous attempts to imagine the origin of protein
synthesis have attributed translocation to conformational changes between the charged and uncharged
states of tRNA (Woese 1970, 1979; Crick et el. 1976) or
have dispensed with translocation altogether (Crothers
1982). In contrast, we suggest that tRNA is relatively
inflexible, and that translocation reflects the differential
affinity of the ribosome for the charged and uncharged
states of tRNA. For example, the ribosome might discriminate between charged and uncharged tRNA by
forming hydrogen bonds to the ester linkage in amino-
Downloaded from symposium.cshlp.org on May 17, 2016 - Published by Cold Spring Harbor Laboratory Press
P E P T I D E - S P E C I F I C RIBOSOMES
acyl- or peptidyl-tRNA. Finally, we note that translocation of tRNA without accompanying translocation of
the internal template could only occur if the peptidespecific ribosome encoded a homopolymer; otherwise,
the same tRNA could not bind first to the A site and
then to the P site.
tRNA Translocation Preceded External Templates
Following peptide bond formation on the modern
ribosome, the peptidyl-tRNA moves from the A to the
P site, and the discharged tRNA moves from the P to
the E site (Nierhaus et al., this volume). Although
translocation was once envisioned as requiring a ratchet
or "gating" mechanism to move the m R N A along the
ribosome one codon at a time, studies with frameshift
suppressor tRNAs demonstrate that a four-base match
between the anticodon and the m R N A results in translocation of the m R N A by four rather than three bases
during a single round of peptide bond formation (Riddle and Carbon 1973; Atkins et al. 1979; Roth 1981;
Bossi and Smith 1984; Weiss et al., this volume). This
strongly implies that movement of the tRNA translocates the mRNA. Thus the m R N A is in effect dragged
along the ribosome as the tRNA moves from the A site
to the P site, and a counting mechanism built into the
tRNA anticodon, rather than into the ribosome or the
m R N A itself, positions the message in the correct reading frame.
Without a preexisting translocation mechanism, a
primitive ribosome could not have translated an external template because random proteins would be synthesized as the m R N A was read in different frames.
This problem cannot be overcome by postulating a
"code without commas" that only allows the m R N A to
be read in one frame (Crick et al. 1957, 1976; Shepard
1983): An m R N A that did not require accurate unidirectional translocation could only encode homopolymers.
We therefore suggest that tRNA translocation
evolved before the advent of external templates, and
that the ability of tRNA translocation to drive m R N A
translocation on the modern ribosome is a molecular
fossil. An important corollary is that prior to the evolution of a template-dependent ribosome, the interaction
between the tRNA anticodon and the internal template
of the ribosome must have become standardized both
in sequence and in codon length. This would not be
implausible if all successful ribosomes descended from
the first ribosome with two contiguous anticodon-binding sites, as described above. Had template-dependent
translation preceded a universal code, ribosomes would
have synthesized random polypeptides as tRNAs using
different genetic codes translated the template.
Was the Three-base Genetic Code Inevitable?
A priori, it is difficult to make an argument against a
two-base code encompassing 16 different amino acids,
or against a redundant four-base code in which
747
covariance of adjacent nucleotides mitigates the potentially harmful effects of a highly redundant code on the
fidelity of translation. However, since a two- or fourbase code could not evolve into a three-base code after
the advent of translocation, it seems likely that the
triplet nature of the modern genetic code was established very early, long before the primitive translation
apparatus could distinguish 16 or more different amino
acids.
We have described a scenario in which an established
population of molecules, the early tRNAs, facilitated
the evolution of protein synthesis. In this case, demands on tRNA structure predated the development of
the code. This leads us to argue that the triplet code
may reflect structural constraints on variation within the
anticodon loop, rather than the necessity of encoding a
relatively large number of amino acids.
Charging Specificity Remained Constant during
Evolution of the Anticodon
It has always been extremely puzzling that the recognition elements for charging by the tRNA synthetase
and for translation are not one and the same. With two
exceptions (the glutamine and methionine tRNA synthetases of E. coli), mutation of the anticodon does not
affect the specificity of charging (see Schimmel 1987 for
review of prokaryotes and yeast; Ho and Kan 1987 for
recent work on aminoacylation of suppressor tRNAs in
vertebrates). The simplest explanation, that structural
constraints prevent simultaneous or coordinate recognition of the CCA acceptor and the anticodon loop by a
tRNA synthetase, seems unlikely on structural
grounds. The distance from the anticodon to the CCA
acceptor group at the opposite end of the L-shaped
tRNA is a little less than 80/~ (Quigley et al. 1978), a
length which could reasonably be spanned by a tRNA
synthetase polypeptide (327-937 residues) or an R N A
enzyme.
More plausibly, the insensitivity of charging specificity to anticodon sequence is a molecular fossil: It tells us
that the anticodon evolved independently of the specificity of charging. In fact, if synthesis of useful polypeptides was the driving force for the evolution of
protein synthesis, then the independence of anticodon
sequence from charging specificity may have been the
result of natural selection: only in this way could translational specificity have been maintained while the
genetic code underwent fine tuning.
Perpetuation of the Peptide-specific Ribosome
An external template like modern mRNA, entirely
separate from the ribosome itself, may well have served
to encode the first heteropolymeric peptides. It is, however, an intriguing possibility that the peptide-specific
ribosome persisted even as the contemporary translation apparatus emerged. For this to occur, the template
for translation would have been an R N A segment that
was physically (and thus genetically) a part of the ribosome itself.
Downloaded from symposium.cshlp.org on May 17, 2016 - Published by Cold Spring Harbor Laboratory Press
748
MAIZELS AND W E I N E R
Prior to the demonstration of messenger RNA (Volkin and Astrachan 1956; Gros et al. 1961; Hall and
Speigelman 1961; Brenner et al. 1962), it was assumed
that ribosomes were peptide-specific, and that each
ribosome translated part of its own RNA sequence into
protein. One great difficulty with such a design, as
pointed out by Jacob and Monod (1961), is that unless
the ribosomes are unstable, the cell relinquishes vast
opportunities for regulation of gene expression. However, a template built into the ribosome itself offers
several distinct advantages for the early evolution of
protein synthesis. First, the ribosome would gain efficient access to the RNA template. Second, the ribosome
would be prevented from translating random RNAs, or
RNAs that were already functioning in a nonmessage
capacity. Third, early ribosomes would be able to carry
internal RNA templates that encoded proteins useful
for the replication of the ribosome themselves (a suggestion made to us by L.E. Orgel). In fact, there are
many contemporary examples of proteins that function
preferentially in cis: subunit II of Q/3 replicase lies at
the 3' end of the single-stranded RNA phage genome,
and prefers to replicate the RNA that encoded it
(Blumenthal and Carmichael 1979); the high rate of
retroposition of mammalian LINE elements (Hattori et
al. t986; Sakaki et al. 1986), as well as insertion elements in lower organisms such as Drosophila (Di Nocera and Casari 1987) and B o m b y x (Burke et al. 1987),
may reflect the preference of the reverse transcriptase
encoded by the element for copying the mRNA from
which it was translated; and the coupling of bacterial
translation to transcription enables transposases to act
preferentially on the D N A encoding them (Morisato et
al. 1983; Derbyshire et al. 1987)9 Fourth, and most
importantly, physical linkage of the ribosome and its
RNA template would guarantee genetic linkage, thereby increasing the chances that both be perpetuated.
If ribosomes and their internal templates did remain
linked in this way, then detachment of the internal
template from the ribosome would be the next landmark in biochemical evolution. This would provide a
genetic origin both for the first external template, or
mRNA, and for the first gene devoted solely to encoding protein.
REFERENCES
Atkins, J., R. Gesteland, B. Reid, and C. Anderson. 1979.
Normal tRNAs promote ribosomal frameshifting. Cell
18: 1119.
Blumenthal, T. and G.C. Carmichael. 1979. RNA replication:
Function and structure of Q/3 replicase. Annu. Rev. Biochem. 48: 525.
Bossi, L. and D. Smith. 1984. Suppressorsufj: A novel type of
tRNA mutant that induces translational frameshifting.
Proc. Natl. Acad. Sci. 81: 6105.
Brenner, S. 1962. RNA, ribosomes, and protein synthesis.
Cold Spring Harbor Syrup. Quant. Biol. 26: 101.
Brenner, S., F. Jacob, and M. Meselson. 1961. An unstable
intermediate carrying information from genes to ribosomes
for protein synthesis. Nature 190: 576.
Burke, W.D., C.C. Calalang, and T.H. Eickbusch. 1987. The
site-specific ribosomal insertion element type II of Bombyx
mori (R2Bm) contains the coding sequence for a reverse
transcriptase-like enzyme9 Mol. Cell. Biol. 7" 2221.
Crick, F.H.C. 1957. Discussion. Biochem. Soc. Symp. 14: 25.
9 1963. The recent excitement in the coding problem9
Prog. Nucleic Acids Res. 1: 164.
Crick, F.H.C9 J.S. Griffith, and L.E. Orgel. 1957. Codes
without commas. Proc. Natl. Acad. Sci. 43' 416.
Crick, F.H.C., S. Brenner, A. Klug, and G. Peiczenik. 1976.
A speculation on the origin of protein synthesis. Origins
Life 7: 389.
Crothers, D.M. 1982. Nucleic acid aggregation geometry and
the possible evolutionary origin of ribosomes and the
genetic code. J. Mol. Biol. 162: 379.
Derbyshire, K.M., L. Hwang, and N.D.F. Grindley. 1987.
Genetic analysis of the interaction of the IS903 transposase
with its terminal inverted repeats. Proc. Natl. Acad9 Sci.
84: 8049.
Di Nocera, P.E and G. Casari. 1987. Related polypeptides are
encoded by Drosophila F elements, I factors, and mammalian L1 sequences9 Proc. Natl. Acad. Sci. 84: 5843.
Fairclough, R9 and C.R. Cantor9 1979. The distance between the anticodon loops of two tRNAs bound to the 70S
Escherichia coli ribosome. J. Mol. Biol. 132: 575.
Gros, F., H. Hiatt, W. Gilbert, C.G. Kurland, R.W. Risebrough, and J.D. Watson9 1961. Unstable ribonucleic acid
revealed by pulse labelling of Escherichia coli. Nature
190: 581.
Hall, B.D. and S. Spiegelman. 1961. Sequence complementarity of T2 DNA and T2-specific RNA. Proc. Natl. Acad.
Sci. 47: 137.
Hattori, M., S. Kuhara, O. Takenaka, and Y. Sakaki. 19869
L1 family of repetitive DNA sequences in primates may be
derived from a sequence encoding a reverse transcriptaserelated protein. Nature 321: 625.
Ho, Y.-S. and Y.W. Kan. 1987. In vivo aminoacylation of
human and Xenopus suppressor tRNAs constructed by
site-specific mutagenesis. Proc. Natl. Acad. Sci. 84: 2185.
Hopfield, J.J. 1978. Origin of the genetic code: A testable
hypothesis based on tRNA structure, sequence, and
kinetic proofreading. Proc. Natl. Acad. Sci. 75: 4334.
Jacob, F. and J. Monod. 1961. Genetic regulatory mechanisms
in the synthesis of proteins. J. Mol. Biol. 3: 318.
Jay, D.G. and W. Gilbert. 1987. Basic protein enhances the
incorporation of DNA into lipid vesicles: Model for the
formation of primordial ceils9 Proc. Natl. Acad. Sci.
84: 1978.
Lacey, J.C. and D.W. Mullins, Jr. 1983. Experimental studies
related to the origin of the genetic code and the process of
protein synthesis - - A review. Origins Life 13: 3.
Moore, P.B. 1985. Polypeptide polymerase: The structure and
function of the ribosome in 1985. In X X I X Welch Foundation Conference on Chemical Research, p. 185. R.A. Welch
Foundation, Houston, Texas.
Morisato, D., J.C. Way, H.-J. Kim, and N. Kleckner. 1983.
Tnl0 transposase acts preferentially on nearby transposon
ends in vivo. Cell 32: 799.
Nierhaus, K.H., H.-J. Rheinberger, U. Geigenm/iller, A.
Gnirke, H. Saruyama, S. Schilling, and P. Wurmbach.
1986. Three tRNA binding sites involved in the ribosomal
elongation cycle. In Structure, function, and genetics of
ribosomes (ed. B. Hardesty and G. Kramer), p. 454.
Springer-Verlag, New York.
Ofengand, J., J9 Ciesiolka, R. Denman, and K. Nurse. 1986.
Structural and functional interactions of the tRNA-ribosome complex. In Structure, function, and genetics of ribosomes (ed. B. Hardesty and G. Kramer), p. 473. SpringerVerlag, New York.
Ptashne, M. 1986. A genetic switch. Cell Press and Blackwell
Scientific Publications, Cambridge, Massachusetts9
Quigley, G.J., M.M. Teeter, and A. Rich. 19789Structural
analysis of spermine and magnesium ion binding to yeast
phenylalanine tRNA. Proc. Natl. Acad. Sci. 75: 64.
Rich, A. 1974. How transfer RNA may move inside the
Downloaded from symposium.cshlp.org on May 17, 2016 - Published by Cold Spring Harbor Laboratory Press
PEPTIDE-SPECIFIC
ribosome. In Ribosomes (ed. M. Nomura et al.), p. 871.
Cold Spring Harbor Laboratory, Cold Spring Harbor, New
York.
Riddle, D.L. and J. Carbon. 1973. Frameshift suppression: A
nucleotide addition in the anticodon of a glycine transfer
RNA. Nature New Biol. 242: 230.
Roth, J.R. 1981. Frameshift suppression. Cell 24: 601.
Sakaki, Y., M. Hattori, A. Fujita, K. Yoshioka, S. Kuhara,
and O. Takenaka. 1986. The LINE-1 family of primates
may encode a reverse transcriptase-like protein. Cold
Spring Harbor Symp. Quant. Biol. 51: 465.
Schimmel, P. 1987. Aminoacyl tRNA synthetases: General
scheme of structure-function relationships in the polypeptides and recognition of transfer RNAs. Annu. Rev.
Biochem. 56: 125.
Shepherd, J.C.W. 1983. From primeval message to presentday gene. Cold Spring Harbor Symp. Quant. Biol.
47: 1099.
Spirin, A.S. and V.I. Lim. 1986. Stereochemical analysis of
ribosomal transpeptidation: Conformation of nascent peptide. J. Mol. Biol. 188: 565.
Steiner, G., R. Liihrmann, and E. Kuechler. 1984. Crosslinking transfer RNA and messenger RNA at the ribosomal
decoding region: Identification of the site of reaction on
the messenger RNA. Nucleic Acids Res. 12: 8181.
Sundaralingam, M., T. Brennan, N. Yathindra, and T. Ich-
RIBOSOMES
749
ikawa. 1975. Stereochemistry of messenger RNA (codon)transfer RNA (anticodon) interaction on the ribosome
during peptide bond formation. In Structure and conformation of nucleic acids and protein-nucleic acid interactions
(ed. M. Sundaralingam and M. Rao), p. 101. University
Park Press, Baltimore.
Van Knippenberg, P.H. 1986. Structural and functional aspects of the N 6, N 6 dimethyladenosines in 16S ribosomal
RNA. In Structure, function, and genetics of ribosomes
(ed. B. Hardesty and G. Kramer), p. 412. Springer-Verlag,
New York.
Volkin, E. and L. Astrachan. 1956. Phosphorus incorporation
in E. coli ribonucleic acid after infection with bacteriophage T2. Virology 2: 146.
Weiner, A.M. and N. Maizels. 1987. tRNA-like structures tag
the 3' ends of genomic RNA molecules for replication:
Implications for the origin of protein synthesis. Proc. Natl.
Acad. Sci. 84: 7383.
Woese, C.R. 1970. The problem of evolving a genetic code.
Bioscience 20: 471.
1979. Just so stories and Rube Goldberg machines:
Speculations on the origin of the protein synthetic machinery. In Structure and conformation of nucleic acids and
protein-nucleic acid interactions (ed. M. Sundaralingam
and M. Rao), p. 357. University Park Press, Baltimore.
Downloaded from symposium.cshlp.org on May 17, 2016 - Published by Cold Spring Harbor Laboratory Press
Peptide-specific Ribosomes, Genomic Tags, and the
Origin of the Genetic Code
N. Maizels and A.M. Weiner
Cold Spring Harb Symp Quant Biol 1987 52: 743-749
Access the most recent version at doi:10.1101/SQB.1987.052.01.083
References
This article cites 34 articles, 14 of which can be accessed free
at:
http://symposium.cshlp.org/content/52/743.refs.html
Article cited in:
http://symposium.cshlp.org/content/52/743#related-urls
Email alerting
service
Receive free email alerts when new articles cite this article sign up in the box at the top right corner of the article or click
here
To subscribe to Cold Spring Harbor Symposia on Quantitative Biology go to:
http://symposium.cshlp.org/subscriptions
Copyright © 1987 Cold Spring Harbor Laboratory Press