Optimization for self-production may explain mysterious features of the ribosome

July 21, 2017
Ribosome
A simulated ribosome (white and purple subunits) processing an amino acid (green). Courtesy Los Alamos National Laboratory

Optimization for self-production may explain key features of ribosomes, the protein production factories of the cell, reported researchers from Harvard Medical School in Nature on July 20.

In a new study, a team led by Johan Paulsson, professor of systems biology at Harvard Medical School, mathematically demonstrated that ribosomes are precisely structured to produce additional ribosomes as quickly as possible, in order to support efficient cell growth and division.

The study's theoretical predictions accurately reflect observed large-scale of ribosomes—revealing why are they made of an unusually large number of small, uniformly sized proteins and a few strands of RNA that vary greatly in size—and provide perspective on the evolution of an exceptional molecular machine.

"The ribosome is one of the most important molecular complexes in all of life, and it's been studied across scientific disciplines for decades," Paulsson said. "I was always puzzled by the fact that it seemed like we could explain its finer details, but ribosomes have these bizarre features that have not often been addressed, or if so in an unsatisfying way."

Every living cell, whether a single bacterium or a human neuron, is a biological system as dynamic and complex as any city. Contained within are walls, highways, power plants, libraries, recycling centers and much more, all working together in unison to ensure the continuation of life.

The vast majority of these myriad structures are made of and made by proteins. And those proteins are made by ribosomes.

Mysterious features

Although scientists have unlocked how ribosomes turn genetic information into proteins at atomic resolution, revealing a molecular machine finely tuned for accuracy, speed and control, it hasn't been clear what advantages lay in several of its large-scale features.

Ribosomes are composed of a puzzlingly large number of different structural proteins—anywhere from 55 to 80, depending on organism type. These proteins are not just more numerous than expected, they are unusually short and uniform in length. Ribosomes are also composed of two to three strands of RNA, which account for up to 70 percent of the total mass of the ribosome.

"Without understanding why collective features exist, it is a bit like looking at a forest and understanding how chloroplasts and photosynthesis work, and not being able to explain why there are trees instead of grass," Paulsson said.

So Paulsson and his collaborators Shlomi Reuveni, an HMS postdoctoral fellow, and Måns Ehrenberg of Uppsala University in Sweden, decided to look at the ribosome in a different light.

"Our breakthrough came by zooming out from the atomic and looking at the ribosome from a new perspective," Reuveni said. "We didn't think of the ribosome as a machine that produces proteins, but rather as the product of the production process."

Forest for the trees

For a cell to divide, it must have two full sets of ribosomes to make all the proteins that the daughter cells need. The speed at which ribosomes can make themselves, therefore, places a hard limit on how fast cell division occurs. Paulsson and his colleagues devised theoretical mathematical models for what the ribosome's features should look like if speed was the primary selective pressure that drove its evolution.

The team calculated that distributing the task of making a new ribosome among many ribosomes—each making a small piece of the final product—can increase the rate of production by as much as 30 percent, since each new ribosome helps make more ribosomes as soon as they are created, accelerating the process.

This represents an enormous advantage for cells that need to divide quickly, such as bacteria. However, the protein production process takes time to initiate, and this overhead cost limits the number of proteins that a ribosome can be made of, according to the math.

The team's models predicted that, for maximum self-production efficacy, a ribosome should be made of between 40 and 80 proteins. Each of these proteins should be around three times smaller than an average cellular protein, and they should all be roughly similar in size.

It turns out that the researchers' theory, developed completely independently of the laboratory, accurately reflects the observed protein composition of the ribosome.

"An analogy for our findings would be to think of ribosomes not as a group of carpenters who merely build a lot of houses, but as carpenters who also build other carpenters," Paulsson said. "There is then an incentive to divide the job into many small pieces that can be done in parallel to more quickly assemble another complete carpenter to help in the process."

Theory and reality

Paulsson and his colleagues also examined ribosomal RNA, which acts as a structural component and carries out the ribosome's enzymatic activity of linking amino acids together into proteins.

Their analysis showed that, the more RNA a ribosome is made of, the more rapidly it can be produced. This is because cells can make ribosomal RNA much faster than protein. Thus, while RNA enzymes are thought to be less efficient than protein enzymes, ribosomes have enormous pressure to use as much RNA as possible to maximize the rate at which more ribosomes can be made.

"Any place the ribosome can get away with using RNA, it should use it because self-production speed can essentially be doubled or tripled," Paulsson said. "Even if RNA were inferior compared to protein for enzymatic function, there is still a great advantage to using RNA if a cell is trying to produce ribosomes as fast as possible."

This observation was predicted to hold primarily for self-producing ribosomes, according to the team. Most other structures in the cell do not self-produce and can sacrifice production speed for the stability and efficacy provided by using protein instead of RNA.

Taken together, the team's theory accurately predicts large-scale features of the that are seen across domains of life. It explains why the fastest growing organisms, such as bacteria, have the shortest ribosomal proteins and the greatest amounts of ribosomal RNA. At the opposite end of the spectrum are mitochondria—the power plants of eukaryotic cells, which are thought to have once been bacteria that entered a permanent symbiotic state. Mitochondria have their own ribosomes that do not produce themselves. Without this pressure, mitochondrial ribosomes are indeed made of larger proteins and far less RNA than cellular ribosomes.

"When we started this project, we didn't have a long list of features that we tried to explain through theory," Reuveni said. "We started with the theory, and certain features emerged. When we looked at data to compare with what our math predicted, we found in most cases that they matched what is seen in nature."

Rather than being mere relics of an evolutionary past, the unusual features of ribosomes thus seem to reflect an additional layer of functional optimization acting on collective properties of its parts, the team writes.

"While this study is basic science, we are addressing something that is shared by all life," Paulsson said. "It is important that we understand where the constraints on structure and function come from, because like much of basic science, it is unpredictable what the consequences of new knowledge can unlock in the future."

Explore further: In creation of cellular protein factories, less is sometimes more

More information: Shlomi Reuveni et al, Ribosomes are optimized for autocatalytic production, Nature (2017). DOI: 10.1038/nature22998

Related Stories

New protein regulated by cellular starvation

April 11, 2017

Researchers at the Center of Genomic Integrity, within the Institute for Basic Science (IBS), have found out an unexpected role for a protein involved in the DNA repair mechanism. The protein SHPRH not only helps to fix mistakes ...

Researchers design first artificial ribosome

July 29, 2015

Researchers at the University of Illinois at Chicago and Northwestern University have engineered a tethered ribosome that works nearly as well as the authentic cellular component, or organelle, that produces all the proteins ...

Recommended for you

New discovery challenges long-held evolutionary theory

October 19, 2017

Monash scientists involved in one of the world's longest evolution experiments have debunked an established theory with a study that provides a 'high-resolution' view of the molecular details of adaptation.

Water striders illustrate evolutionary processes

October 19, 2017

How do new species arise and diversify in nature? Natural selection offers an explanation, but the genetic and environmental conditions behind this mechanism are still poorly understood. A team led by Abderrahman Khila at ...

Gene editing in the brain gets a major upgrade

October 19, 2017

Genome editing technologies have revolutionized biomedical science, providing a fast and easy way to modify genes. However, the technique allowing scientists to carryout the most precise edits, doesn't work in cells that ...

Gut bacteria from wild mice boost health in lab mice

October 19, 2017

Laboratory mice that are given the gut bacteria of wild mice can survive a deadly flu virus infection and fight colorectal cancer dramatically better than laboratory mice with their own gut bacteria, researchers report October ...

8 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

barakn
Jul 21, 2017
This comment has been removed by a moderator.
torbjorn_b_g_larsson
5 / 5 (2) Jul 21, 2017
Yes,I would like to think so, I have not read the paper yet. But I had Måns as course assistant in molecular biology way back. =D
Whydening Gyre
5 / 5 (1) Jul 22, 2017
Yes,I would like to think so, I have not read the paper yet. But I had Måns as course assistant in molecular biology way back. =D

LTNS, Torbjorn! Welcome back!
Always appreciate your input!
Ojorf
not rated yet Jul 22, 2017
This is just so cool!
I love how we all have these minute little machines rushing around at a frantic pace building structures and dismantling others, things zipping around all over the place. Biology seems so mechanical at this scale far, far beyond our natural senses.
It's great that they managed to build their theory/model before testing it against the real world, wonderful science.
It's almost uncanny how the world works following mathematical rules so precisely. How something that seems confusing or puzzling or inexplicable can suddenly become clear just looking at it in the right way and applying the correct math and theory.
How could anyone possibly think that god did it?
thingumbobesquire
not rated yet Jul 22, 2017
This study falls in line with the classical principle of biospheric optimization and growth that living systems taken as a whole exhibit the quality of least action for maximum development potential.
Whydening Gyre
not rated yet Jul 22, 2017
This is just so cool!
I love how we all have these minute little machines rushing around at a frantic pace building structures and dismantling others, things zipping around all over the place. Biology seems so mechanical at this scale far, far beyond our natural senses.

It's almost uncanny how the world works following mathematical rules so precisely. How something that seems confusing or puzzling or inexplicable can suddenly become clear just looking at it in the right way and applying the correct math and theory.
How could anyone possibly think that god did it?

If your god is (G)eometricae (O)rdinatim (D)atum... Well, then - a god DID do it...:-)
EmceeSquared
not rated yet Jul 24, 2017
Interesting that these self-replicating ribosomes are made preferentially of RNA, believed to be the first self-replicating molecule on Earth. In a way, the RNA/ribosome dyad is the dance of all Earth life, with the surrounding bodies and their lives just incidental byproducts.
barakn
not rated yet Jul 28, 2017
A moderator removed my comment "This is exceptional work," labeling it as "POINTLESS VERBIAGE." Since any comment is basically nothing but verbiage, I've come to the conclusion that POINTLESSNESS=BREVITY. Should I have added an adverb to make it longer? "This is very exceptional work" doesn't sound right: something is either exceptional or it is not. Ironically, phys.org used to have a rating system for the articles themselves which allowed any user to do what I did: succinctly rate the quality of an article or the scientific work that is its subject. If one were to judge the quality of my comment, one might start by noticing that Torbjorn, one of the most highly rated and clearly one of the smartest commenters on phys.org, was the next person to comment and did so as a reply to my comment, essentially agreeing with me, and that the rest of the comments suggest the readers liked the article and found it interesting or in line with their own thinking on the subject.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.