Looking for the Origin of Life Inside a 4 Billion-Old Molecular Machine
How did life on Earth originate from simple molecules? This question is one of the deepest, most fundamental questions of science, and it remains unanswered.
In Georgia Tech’s College of Sciences, scientists are trying to decipher the origin of life. Among them is Loren D. Williams, a professor in the School of Chemistry and Biochemistry and a member of the Parker H. Petit Institute of Bioengineering and Biosciences.
For Williams, part of the answer has to come from the ribosome. This gigantic molecular machine comprising ribonucleic acids (RNA) and proteins enables a key distinction of life: translation of genetic information to proteins.
How did translation begin? Work in Williams' lab suggests that translation is the product of molecular symbiosis, that ancestors of RNA and protein were molecular symbionts, and that life arose from the coevolution of proteins and RNA. That startling notion challenges the popular “RNA world” hypothesis of the origin of life. That world posits a time when life was based only on RNA, RNA-catalyzed transformations, and RNA-based genetic material; proteins, the ribosome, and translation appeared later.
At the meeting of the American Chemical Society in Philadelphia, Williams makes the case that the early history of the ribosome is also the history of the origin of life.
Williams and his coworkers base their conclusions on meticulous analysis of the “fossil record” in all ribosomes. As trees imprint events in their rings, or ice cores suspend time by preserving matter in frozen columns, ribosomes are time machines, Williams says, one “that allows us to look at the behaviors of ancient molecules 3.8 billion years ago.”
Crystal structures indicate that the modern ribosome grew by accretion, Williams says. By peeling away the layers deposited in the ribosome over almost 4 billion years, Williams and coworkers reached inside the so-called common core, which is the common denominator and oldest part of biology. Deep inside is the peptidyl transferase center, which links amino acids through peptide bonds “This part of the ribosome originates in chemistry,” Williams says. “It is pre-biology.”
If two amino acids are located within the peptidyl transferase center, they will easily form a peptide bond. “But as soon as you do that in the absence of the ribosome, the ends of the amino acids come together, forming a cyclic structure,” Williams says. Polymers cannot form. But if the ends are kept apart, by the primitive ribosome, a chain of peptide bonds could grow into a polymer.
As it happens, a feature of the ancient ribosome is a hole in the middle, foreshadowing the tunnel through which proteins leave modern ribosomes after they are made. “We think that an original function of the ribosome was not to catalyze peptide bond formation but to keep amino acids from forming cyclic structures and thereby form longer peptides,” Williams says.
The tunnel through which all proteins pass is a constant in the evolution of the ribosome. By examining crystal structures and mapping how modern ribosomes grew from the common core, Williams gleaned that ribosomes evolved to make this tunnel long and rigid.
Why? Williams suggests that without a long tunnel, a synthesized protein would fold at once, become active, and start eating the ribosome’s structure. “The tunnel is saying to the protein, no you cannot become functional yet.”
Ribosome crystal structures suggest something else: When early ribosomes made small peptides that were not capable of folding, some of these peptides stuck to and accreted on the ribosome. “We think the ribosome started making peptides in the first place to give itself greater stability,” Williams says. In making peptides that became bound to the ribosome like scaffolding, the ribosome became bigger and more stable.
As evidence, Williams presents the protein fossils in ribosomes. The oldest ones are frozen random coils “That’s the first thing we think the ribosome made. They got stuck, they didn’t fold. They don’t look like modern proteins.”
Next are isolated beta hairpins. “Nowhere else in biology will you see isolated beta hairpins without other protein around it,” Williams notes. “Only in the core of the ribosome do you see beta hairpins surrounded by RNA.” These isolated beta hairpins are the most ancient folded proteins in biology, he says.
Then come more modern proteins, made of beta sheets and alpha helices, with hydrophobic exteriors and hydrophilic interiors and the ability to fold to globular forms.
“Our results show that protein folding from random-coil peptides to functional polymeric domains was an emergent property of the interactions of ribosomal RNA and peptides,” Williams says. “The ribosome is the cradle of protein evolution.”
Along with Nicholas V. Hud, a professor at the School of Chemistry and Biochemistry and the director of the Center for Chemical Evolution, Williams and other origin-of-life researchers in Georgia Tech propose that chemical evolution—driven by assembly and other processes that increase stability—gradually converted to biological evolution, involving genes, enzymes, and ribosomes.
“We believe that chemical evolution was driven by assembly,” Williams says. “In biology, things that are assembled live longer chemically than those that are not. A folded protein is chemically stable. Unfold it, and it falls apart.” So it was in chemical evolution. Things that could assemble existed longer than those that couldn’t.
“If you had a molecule that could assemble and make peptides that bound to it, and they co-assemble, all of a sudden you have something better,” Williams says. “We think the reason proteins came into biology was that they stabilized the ribosome and protected it from degradation. The ribosome was looking out for itself. It was an evolutionary process by the ribosome, for the ribosome, and of the ribosome.
“We have the historical record or molecules. These things are preserved in the ribosome, we can see them. There is a molecular record of the origin of life.”
The evolution of the ribosome, illustrating growth of the large (LSU) and small (SSU) subunits, first as separate units and eventually as parts of a whole.
In Phase 1, ancestral RNAs form stem loops and minihelices. In Phase 2, LSU, which has a short tunnel, condenses short, nonspecific, peptide-like oligomers. Some of these oligomers bind back onto the ribosome and stabilize it. At this point, SSU may have a single-stranded RNA-binding function. In Phase 3, the subunits associate, mediated by the expansion of tRNA from a minihelix to its modern L-shape. The tunnel elongates. In Phase 4, the two subunits associate and they evolve together. The ribosome is a noncoding diffusive ribozyme in which proto-mRNA and the SSU act as positioning cofactors, producing peptide-like oligomers, some of which form beta-hairpins. In Phase 5, the ribosome expands to an energy-driven, translocating, decoding machine. Phase 6 marks completion of the common core with a proteinized surface (the proteins are omitted for clarity). mRNA is shown in light green. The A-site tRNA is magenta, the P-site tRNA is cyan, and the E-site tRNA is dark green.
A. Maureen Rouhi