In the beginning—of the ribosome, the cell’s protein-building workbench—there
were ribonucleic acids, the molecules we call RNA that today perform a host of
vital functions in cells. And according to a new analysis, even before the
ribosome’s many working parts were recruited for protein synthesis, proteins
also were on the scene and interacting with RNA. This finding challenges a
long-held hypothesis about the early evolution of life.
The study appears in PLoS ONE.
The RNA world hypothesis, first promoted in 1986 in a paper in Nature and defended and elaborated on for more than 25 years,
posits that the first stages of molecular evolution involved RNA and not
proteins, and that proteins (and DNA) emerged later, said University of
Illinois crop sciences and Institute for Genomic Biology professor Gustavo
Caetano-Anollés, who led the new study.
“I’m convinced that the RNA world (hypothesis) is not correct,”
Caetano-Anollés said. “That world of nucleic acids could not have existed if
not tethered to proteins.”
The ribosome is a ribonucleoprotein machine, a complex that can have as
many as 80 proteins interacting with multiple RNA molecules, so it makes sense
that this assemblage is the result of a long and complicated process of gradual
co-evolution, Caetano-Anollés said. Furthermore, “you can’t get RNA to perform
the molecular function of protein synthesis that is necessary for the cell by
Proponents of the RNA world hypothesis make basic assumptions about the
evolutionary origins of the ribosome without proper scientific support,
Caetano-Anollés said. The most fundamental of these assumptions is that the
part of the ribosome that is responsible for protein synthesis, the peptidyl
transferase center (PTC) active site, is the most ancient.
In the new analysis, Caetano-Anollés and graduate student Ajith Harish (now
a postdoctoral researcher at Lund University in Sweden) subjected the universal protein
and RNA components of the ribosome to rigorous molecular analyses—mining them
for evolutionary information embedded in their structures. (They also analyzed
the thermodynamic properties of the ribosomal RNAs.)
They used this information to generate timelines of the evolutionary
history of the ribosomal RNAs and proteins.
These two, independently generated “family trees” of ribosomal proteins and
ribosomal RNAs showed “great congruence” with one another, Caetano-Anollés
said. Proteins surrounding the PTC, for example, were as old as the ribosomal
RNAs that form that site. In fact, the PTC appeared in evolution just after the
two primary subunits that make up the ribosome came together, with RNA bridges
forming between them to stabilize the association.
The timelines suggest that the PTC appeared well after other regions of the
protein-RNA complex, Caetano-Anollés said. This strongly suggests, first, that
proteins were around before ribosomal RNAs were recruited to help build them,
and second, that the ribosomal RNAs were engaged in some other task before they
picked up the role of aiding in protein synthesis, he said.
“This is the crucial piece of the puzzle,” Caetano-Anollés said. “If the
evolutionary buildup of ribosomal proteins and RNA and the interactions between
them occurred gradually, step-by-step, the origin of the ribosome cannot be the
product of an RNA world. Instead, it must be the product of a ribonucleoprotein
world, an ancient world that resembles our own. It appears the basic building
blocks of the machinery of the cell have always been the same from the
beginning of life to the present: evolving and interacting proteins and RNA
“This is a very engaging and provocative article by one of the most
innovative and productive researchers in the field of protein evolution,” said
University of California at San Diego research professor Russell Doolittle, who
was not involved in the study. Doolittle remains puzzled, however, by “the
notion that some early proteins were made before the evolution of the ribosome
as a protein-manufacturing system.” He wondered how—if proteins were more
ancient than the ribosomal machinery that today produces most of them—”the
amino acid sequences of those early proteins were ‘remembered’ and incorporated
into the new system.”
Caetano-Anollés agreed that this is “a central, foundational question” that
must be answered.
“It requires understanding the boundaries of emergent biological functions
during the very early stages of protein evolution,” he said. However, he said, “the proteins that catalyze non-ribosomal protein synthesis—a complex and
apparently universal assembly-line process of the cell that does not involve
RNA molecules and can still retain high levels of specificity—are more ancient
than ribosomal proteins. It is therefore likely that the ribosomes were not the
first biological machines to synthesize proteins.”
Caetano-Anollés also noted that the specificity of the ribosomal system “depends on the supply of amino acids appropriately tagged with RNA for
faithful translation of the genetic code. This tagging is solely based on
proteins, not RNAs,” he said. This suggests, he said, that the RNA molecules
began as co-factors that aided in protein synthesis and fine-tuned it, resulting
in the elaborate machinery of the ribosome that exists today.