Defying textbook science, study finds new role for proteins

January 1, 2015, University of Utah Health Sciences
A new finding goes against dogma, showing for the first time that the building blocks of a protein, called amino acids, can be assembled by another protein, and without genetic instructions). The Rqc2 protein (yellow) binds tRNAs (dark blue, teal) which add amino acids (bright spot in middle) to a partially made protein (green). The complex binds the ribosome (white). Credit: Janet Iwasa, Ph.D., University of Utah

Open any introductory biology textbook and one of the first things you'll learn is that our DNA spells out the instructions for making proteins, tiny machines that do much of the work in our body's cells. Results from a study published on Jan. 2 in Science defy textbook science, showing for the first time that the building blocks of a protein, called amino acids, can be assembled without blueprints - DNA and an intermediate template called messenger RNA (mRNA). A team of researchers has observed a case in which another protein specifies which amino acids are added.

"This surprising discovery reflects how incomplete our understanding of biology is," says first author Peter Shen, Ph.D., a postdoctoral fellow in biochemistry at the University of Utah. "Nature is capable of more than we realize."

To put the new finding into perspective, it might help to think of the cell as a well-run factory. Ribosomes are machines on a protein assembly line, linking together in an order specified by the genetic code. When something goes wrong, the ribosome can stall, and a quality control crew is summoned to the site. To clean up the mess, the ribosome is disassembled, the blueprint is discarded, and the partly made protein is recycled.

Yet this study reveals a surprising role for one member of the quality control team, a protein conserved from yeast to man named Rqc2. Before the incomplete protein is recycled, Rqc2 prompts the ribosomes to add just two amino acids (of a total of 20) - alanine and threonine - over and over, and in any order. Think of an auto assembly line that keeps going despite having lost its instructions. It picks up what it can and slaps it on: horn-wheel-wheel-horn-wheel-wheel-wheel-wheel-horn.

"In this case, we have a protein playing a role normally filled by mRNA," says Adam Frost, M.D., Ph.D., assistant professor at University of California, San Francisco (UCSF) and adjunct professor of biochemistry at the University of Utah. He shares senior authorship with Jonathan Weissman, Ph.D., a Howard Hughes Medical Institute investigator at UCSF, and Onn Brandman, Ph.D., at Stanford University. "I love this story because it blurs the lines of what we thought proteins could do."

Like a half-made car with extra horns and wheels tacked to one end, a truncated protein with an apparently random sequence of alanines and threonines looks strange, and probably doesn't work normally. But the nonsensical sequence likely serves specific purposes. The code could signal that the partial protein must be destroyed, or it could be part of a test to see whether the ribosome is working properly. Evidence suggests that either or both of these processes could be faulty in neurodegenerative diseases such as Alzheimer's, Amyotrophic lateral sclerosis (ALS), or Huntington's.

"There are many interesting implications of this work and none of them would have been possible if we didn't follow our curiosity," says Brandman. "The primary driver of discovery has been exploring what you see, and that's what we did. There will never be a substitute for that."

The scientists first considered the unusual phenomenon when they saw evidence of it with their own eyes. They fine-tuned a technique called cryo-electron microscopy to flash freeze, and then visualize, the quality control machinery in action. "We caught Rqc2 in the act," says Frost. "But the idea was so far-fetched. The onus was on us to prove it."

It took extensive biochemical analysis to validate their hypothesis. New RNA sequencing techniques showed that the Rqc2/ribosome complex had the potential to add amino acids to stalled proteins because it also bound tRNAs, structures that bring amino acids to the assembly line. The specific tRNAs they saw only carry the amino acids alanine and threonine. The clincher came when they determined that the stalled proteins had extensive chains of alanines and threonines added to them.

"Our job now is to determine when and where this process happens, and what happens when it fails," says Frost.

Explore further: Scientists discover why some proteins are speedier than others

More information: Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains. Peter S. Shen, Joseph Park, Yidan Qin, Xueming Li, Krishna Parsawar, Matthew H. Larson, James Cox, Yifan Cheng, Alan M. Lambowitz, Jonathan S. Weissman, Onn Brandman, Adam Frost. Science, Jan. 2, 2015. www.sciencemag.org/lookup/doi/ … 1126/science.1259724

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imido
Jan 01, 2015
This comment has been removed by a moderator.
Bongstar420
5 / 5 (7) Jan 01, 2015
Its not surprising, and Imido is painting an inaccurate picture by injecting words which imply incorrect understandings.
Uncle Ira
5 / 5 (7) Jan 01, 2015
Its not surprising, and Imido is painting an inaccurate picture by injecting words which imply incorrect understandings.


Well that is just what the Zephir-Skippy does. You get used to it.
Uncle Ira
4 / 5 (4) Jan 02, 2015
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What's with you Skippy? Aunty-Natalie-Skippy can't write for her self? Maybe she should have spent some of the Mercedes money on a new full time computer, that way she could tell us about her magic money her self.
Jim4321
5 / 5 (9) Jan 02, 2015
One of the stumbling blocks to a naturalistic study of the origin of life has been understanding how proteins were assembled initially. The machinery using ribosomes is quite coimplex and its hard to see how it could have evolved in the absence of some other protein assembly mechanism. This paper shows that one protein can help assemble another protein. Perhaps, it gives a clue to how proteins were originally assembled -- with the help of other proteins. This would avoid some of the complexity associated with ribosomes. Great Paper.
Torbjorn_Larsson_OM
5 / 5 (3) Jan 03, 2015
"Before the incomplete protein is recycled, Rqc2 prompts the ribosomes to add just two amino acids (of a total of 20) - alanine and threonine - over and over, and in any order."

So it doesn't break Crick's Central Dogma, that sequence information put into a protein does not make it out again.

It looks more like evolution saw a handy signal: "... the nonsensical sequence likely serves specific purposes. The code could signal that the partial protein must be destroyed, or it could be part of a test to see whether the ribosome is working properly."

By the way, did an anti-scientist troll comment finally got removed? Good grief, maybe the discussion can be informative on science this time!
Torbjorn_Larsson_OM
4 / 5 (4) Jan 03, 2015
@jim4321: I initially thought it could show mechanisms of a pre-RNA world too, amino acids being energetically easier and so likely evolved (or co-opted from Miller mechanism sources) before nucleotides. But note how they claim it uses the present, not yet disassembled ribosome to do the deed.

I don't think initial assembly of proteins is much of a stumbling block any longer. There are several signs that early proteins were unordered, such that an 11 mer random polypeptide structural element in the preserved ribosome core. And attempted phylogenies of the ribosome, that works so well to elucidate the general tree, seems to dig down to that period. After uncovering an expansion fingerprint ("insertion fingerprints"), they can see how the large ribosomal unit (LSU) started out as a simple RNA string with a kink defect.

[tbctd]
Torbjorn_Larsson_OM
5 / 5 (3) Jan 03, 2015
[ctd]

The ribosome kink evolved into the phosphate enzymatic P site. This is consistent with how perserved rRNA and tRNA has generic catalytic function in Hadean ocean conditions (anoxic, FeII solute), they started out from the ribosyme pool after genetic takeover of RNA.

Later a tunnel evolved for polypeptide products. After evolving a docking pad for the small ribosomal unit (SSU), it evolved translocation functions (remaining tRNA binding sites), the origin of the genetic code. ["Evolution of the ribosome at atomic resolution", Petrov et al, PNAS EE 2014]

[tbctd]
Torbjorn_Larsson_OM
5 / 5 (3) Jan 03, 2015
[ctd]

Such history suggest that the ribosome initial function could have been to provide tRNA with enzymatic dipeptide cofactors. Cofactors are continually freed by hydrolysis, and sometimes it produced longer polypeptides. Unordered peptide "nests" find use as they can bind catalytic metal atoms when 5-6 mers long. Longer random polypeptides spontaneously make amyloid sheets that can function as structural members (membranes).

And of course a LSU/SSU coevolution that started to produce ordered proteins could extend use.

[tbctd]
Torbjorn_Larsson_OM
5 / 5 (3) Jan 03, 2015
[ctd]

This putative history fits well into alkaline hydrothermal vent emergence of life by the way.

- Using peptide membranes to patch the inorganic ones and fixate early metabolic engine atoms would amp up metabolic production. We had genetic takeover happen already when the ribosome ancestor appears in the replicator pool. So now RNA replication would hinge on stabilizing and maximizing metabolism.

And of course at the time the cells could build organic membranes they could start to divide, and that would usher in a phase change from evolution of string replicators to cell replicators.

- The alkaline hydrothermal emergence predicts nucleotide appearance last, from the free energy requirement to make them. And it has an inherent thermoreactor (convection, diffusion and catalytic metal atoms) for PCR amplification of RNA strings.

[tbctd]
Torbjorn_Larsson_OM
5 / 5 (3) Jan 03, 2015
[ctd]

The remaining problem (as I see it) is how the initial replicator pool dealt with the racemic problems. We see in the lab that coevolving strings are more productive, and that the shortest replicators appears when they non-intuitively replicate the other chirality nucleotide strings. (That is, take over the catalysis from metal atoms.)

But this is still problematic due to the chiral lockup problem. (Binding the reverse chirality nucleotide block string replication.)

Not in the sense that replication doesn't happen at all, I think. But it seems very unproductive and slow, maybe too slow to be the pathway taken. As a comparison, a single chirality single strand replicator appears within 30 kyrs in chemical simulations when you have a vent PCR reactor available.

[tbctd]
Torbjorn_Larsson_OM
5 / 5 (3) Jan 03, 2015
[ctd]

I hope someone can check this, see if there is more to learn on the event of chiral breaking. It is oddly unplaced. It happened latest at the evolution of the genetic code I think. It would be asking for much finetuning to have chiral ribosomes evolve in lockstep to support a racemic doubled metabolism.

But illustratively the lipid membrane metabolism phylogeny seems to have started out with racemic lipid membranes, later specializing in the split Bacteria and Archaea lineages. We are talking DNA genes, so this is later. Early carbon uptake seems to have been doubled metabolically as well, splitting the CO2+CH4 root metabolism into the CO2 acetogenic and the CH4 metanophilic ones we see today. This is later too, as this is another Bacteria/Archaea specialization as far as vertical gene inheritance goes.

In all cases dumping the early robust but inefficient double metabolisms could happen as the replicators became more proficient in controlling their environment.
JVK
1 / 5 (5) Jan 03, 2015
Two weeks ago we learned about the importance of protein folding to DNA stability in organized genomes.

Now we learn about the importance of protein folding to links from metabolic networks to genetic networks that appear to involve RNA-directed DNA methylation and RNA-mediated events. The RNA-mediated events link amino acid substitutions to differentiation of all cell types of all individuals of all species.

When do you think everyone will realize that what is known about physics and chemistry in the context of ecological variation and ecological adaptations has eclipsed the pseudoscientific nonsense about mutations and evolution that is still touted by some evolutionary theorists?

The theorists are spreading their discussions across many different groups -- too many to contend with. Makes no difference.

The outcome of the discussions must integrate physics, chemistry, and conserved molecular mechanisms.
Vietvet
5 / 5 (8) Jan 03, 2015
@jvk

No doubting the importance of protein folding.

Three years ago last Oct. my high school sweetheart's father died from Alzheimer's. That led me to research everything I could find about that insidious disease. That led me protein folding and the pathologies that can result from mis-folding. That led me to Stanfords Folding@Home.

I've been running their program on my pc 24/7 ever since.

I suggest you do the same. That way you could do little something scientifically positive for a change.

http://folding.stanford.edu/

JVK
1 / 5 (7) Jan 03, 2015
See:
Pheromones and the luteinizing hormone for inducing proliferation of neural stem cells and neurogenesis http://www.freshp...8009.php

I'm rather certain that they abandoned this patent because too many science idiots, like you, did not understand the importance of protein folding in the context of thermodynamic cycles of protein biosynthesis and degradation that link perturbed protein folding to pathology.

For contrast, my first presentation to a scientific forum was in 1992: Luteinizing hormone: The link between sex and the sense of smell?

As you may know, the loss of olfactory acuity and specificity in neurodegenerative diseases can be diagnostic. However, you and others may not know how that fact is linked to Alzheimer's because you are science idiots.

I presented to serious scientists at Anti-Aging Medicine Conferences in 1994 before book publication and in 1995 after publication.
JVK
1 / 5 (5) Jan 03, 2015
The Scent of Eros: Mysteries of Odor in Human Sexuality
http://www.amazon...9523383X

That way you could do little something scientifically positive for a change.


Search for Alzheimer and compare what I've been doing for the past 40 years, and 20 years since book publication, to the amount of pseudoscientific nonsense you have touted during your lifetime, and the harm you have caused.

Your high school sweetheart's father might have received effective treatment if not for those who believe that mutations can be beneficial.
JVK
1 / 5 (7) Jan 03, 2015
We cited Doty's work with Alzheimer's. He published "The Great Pheromone Myth" in 2010 with claims that it

"...directly challenges ideas about the role chemicals play in mammalian behavior and reproductive processes. It is a must-have reference for biologists, psychologists, neuroscientists, and readers interested in animal behavior, ecology, and evolution."

You may wonder why your high school sweetheart's father lost his appetite for food, which was due to loss of olfaction. But science idiots like you and Doty never ask if the loss of kin recognition abilities is linked to the sense of smell via pheromones as it is in all other species on the planet.

Can you imagine what a non-invasive treatment with pheromones could do to increase hippocampal neurogenesis, learning, and memory compared to neural stem cell replacement?

I can, because I am not a science idiot. See: http://medicalxpr...ins.html
Vietvet
4.5 / 5 (8) Jan 03, 2015
@jvk

""You may wonder why your high school sweetheart's father lost his appetite for food, which was due to loss of olfaction. ""

You're an asshole.

He never lost his appetite.

You just proved you don't know shit about Alzheimer's---or anything else.
Captain Stumpy
4.5 / 5 (8) Jan 04, 2015
When do you think everyone will realize that what is known about physics and chemistry in the context of ecological variation and ecological adaptations has eclipsed the pseudoscientific nonsense about mutations and evolution that is still touted by some evolutionary theorists?
1- your model CAUSES MUTATIONS, so your argument is fallacious right from the start (means: you lie & ignore empirical evidence)
2- The THEORY of EVOLUTION is still on firm ground as it incorporates scientific principles and is validated by empirical evidence as well as experimentation (See Lenski & Extavour)
3- your model is simply a small part supporting the Theory of EV as it demonstrates beneficial MUTATIONS

lastly, and most importantly
The Scent of Eros:
THIS is called SPAM and PSEUDOSCIENCE

you want extra clicks generating income
go pay Google like everyone else
Captain Stumpy
4.5 / 5 (8) Jan 04, 2015
Can you imagine ...
I can, because I am not a science idiot
We have been able to demonstrate, beyond the shadow of a doubt, that you are not only IGNORANT of a great number of biological factors (being that you are seriously confused about epigenetics and a few other things) but we have also DEMONSTRATED that you are not able to remember or comprehend the lexicon used by your own chosen field

this is NOT debatable as we can prove, continually, that you ignore simple definitions in your own field that are used for clear, concise communication

you CHOOSE to ignore these things, which makes you STUPID
thus, by definition, you are, in your own words, "a science idiot"

Please observe Torbjorn_Larsson_OM, Anonymous9001, or Antialias_Physorg for examples of scientific integrity, honesty and intelligence

Whydening Gyre
5 / 5 (5) Jan 04, 2015
Can you imagine ...
I can, because I am not a science idiot
We have been able to demonstrate, beyond the shadow of a doubt, that you are not only IGNORANT of a great number of biological factors (being that you are seriously confused about epigenetics and a few other things) but we have also DEMONSTRATED that you are not able to remember or comprehend the lexicon used by your own chosen field

this is NOT debatable as we can prove, continually, that you ignore simple definitions in your own field that are used for clear, concise communication

you CHOOSE to ignore these things, which makes you STUPID
thus, by definition, you are, in your own words, "a science idiot"

Please observe Torbjorn_Larsson_OM, Anonymous9001, or Antialias_Physorg for examples of scientific integrity, honesty and intelligence


On the job early I see, Cap'n...:-)
OZGuy
5 / 5 (7) Jan 04, 2015
JVK
I always thought of you as a snake oil salesman and a NASTY one to boot. So now are you going to start selling your scent, lets be honest here it is NOT human pheromones, on quack medical sites to drain the pockets of the desperate relatives of terminally ill patients?

Stick to conning gullible horny schoolboys, they probably won't sue you, relatives of the terminally ill tend to be less forgiving when promised benefits don't materialise.
Torbjorn_Larsson_OM
5 / 5 (6) Jan 04, 2015
Okay, I think we had an interesting thread. But of course the pheromone troll had to sniff it out.

Unfortunately his anti-science trollish behavior hasn't evolved. It isn't even worth reading. The usual trollish fare is comical but he behaves as a lout. (See his attempt to describe Alzheimer here.)

@Vietvet: "No doubting the importance of protein folding."

Indeed. Therefore it was with interest I read the article some weeks back where they showed a signal that can be used to show that protein folding has been under intense evolutionary pressure ever since protein folds were hit on. [I have the ref somewhere, but my computer is behaving badly today...]

That is of course complementary to the phylogeny of the ribosome, since other folding mechanisms (such as chaperone proteins) are physically separated and evolved later (younger genes).
Jim4321
5 / 5 (4) Jan 04, 2015
@Torbjorn Thanks for the discussion of evolution of the ribosome. My general knowledge in this area is 20 or 30 years out of date. It will be fun to follow the trail you have liad out.

Jim
JVK
1 / 5 (4) Jan 04, 2015
http://www.nature...SF3.html

Excerpt 1) Dots represent amino acid differences... not an inferred ancestor.

Excerpt 2) Extracellular loops are oriented up and cytoplasmic loops are oriented down.

Everything known about feedback loops, chromatin loops, and RNA-mediated events links the epigenetic landscape to the physical landscape of DNA via the bio-physically constrained chemistry of protein folding.

http://www.nature...964.html

Excerpt: "...host shifts... play a key role in the formation of new species50."

The host shifts are nutrient-dependent and pheromone-controlled.

Conclusion: "Olfaction and odor receptors provide a clear evolutionary trail that can be followed from unicellular organisms to insects to humans..." http://www.ncbi.n...3960071/

The complexity of their RNA-mediated folding shows us proteins do not evolve.
JVK
1 / 5 (4) Jan 04, 2015
http://www.nature...306.html

"We cannot conceive of a global external factor that could cause, during this time, parallel evolution of amino acid compositions of proteins in 15 diverse taxa that represent all three domains of life and span a wide range of lifestyles and environments. Thus, currently, the most plausible hypothesis is that we are observing a universal, intrinsic trend that emerged before the last universal common ancestor of all extant organisms."

Alternatively, "...genomic conservation and constraint-breaking mutation is the ultimate source of all biological innovations and the enormous amount of biodiversity in this world." (p. 199) http://www.amazon...99661731

Only the biologically uninformed will continue to tout ridiculous theories now that details are clear about the involvement of RNA-directed DNA methylation and RNA-mediated amino acid substitutions that differentiate cell types are clear.
JVK
1 / 5 (4) Jan 04, 2015
What's clear is that "Nutrient-dependent/pheromone-controlled adaptive evolution: a model" links the bio-physically constrained nutrient-dependent chemistry of protein folding from light-induced amino acid substitutions in plants and animals to nutrient-dependent amino acid substitutions fixed in the DNA of organized genomes of all animals via their pheromone-controlled physiology of reproduction. http://www.ncbi.n...24693353

That fact has been clear to some researchers since we first detailed what was known about RNA-mediated cell type differentiation in the molecular epigenetics section of our 1996 Hormones and Behavior review article: From Fertilization to Adult Sexual Behavior http://www.hawaii...ion.html

Only science idiots continue to think they can link physics, chemistry and conserved molecular mechanisms in the context of the pseudoscientific nonsense touted by Torbjorn_Larsson_OM
Captain Stumpy
4 / 5 (4) Jan 04, 2015
What's clear is that "Nutrient-dependent/pheromone-controlled adaptive evolution: a model" links
What it MODELS is mutations

What you forget to post when you talk about science idiocy is your continual choice to remain blatantly stupid with regard to clear concise terminology used by real, ACTUAL scientists like Lenski and Extavour

What you always fail to do is remind people that
I refuse to accept definitions and assumptions about mutations!
so, because of this, you make sh*t up as you go and wing it, terminology wise, creating your own personal nomenclature for things which is why you promote PSEUDOSCIENCE, and not actual science

what you are is TROLLING and BAITING

you are nothing more than an egotistical narcissistic TROLL trying to push a religion onto science advocates by bullying them and spamming with your Porn-scentBS-site

I will continually remind you of this until you are banned for pseudoscience, trolling and spam
JVK
1 / 5 (4) Jan 04, 2015
Mapping Social Behavior-Induced Brain Activation at Cellular Resolution in the Mouse
http://www.cell.c...)01043-2

See also: From Fertilization to Adult Sexual Behavior
http://www.hawaii...ion.html
Others have now discovered the link from c-fos

"Intracerebral GnRH response. Mammalian pheromones from opposite sex conspecifics typically influence a pulsatile intracerebral GnRH response (Meredith and Fernandez-Fewell, 1994) and subsequent increases in serum LH and/or testosterone in the males of several mammalian species (Meredith and Howard, 1992). Similarly, male pheromones may influence the LH secretion of females (Vandenbergh, 1994). Supporting these findings, olfactory stimuli appear to activate the immediate early gene c-fos (Guthrie, Anderson, Leon, and Gall, 1993). In signal transduction systems, c-fos appears to couple short-term intracellular signals..."
Captain Stumpy
4 / 5 (4) Jan 05, 2015
Mapping Social Behavior-Induced
I will ask this again, since you are refusing to answer this same question elsewhere when you posted this EXACT same thing

HOW does this in ANY WAY support your anti-science diatribe?
How does this prove your anti-mutation or anti-Theory of Evolution posts?

OR
is this another redirect?
like you did here with regard to Moss? http://phys.org/n...firstCmt

You chose a dead guy and started making claims knowing that no one can contact him to verify or validate your claims

That is a really pathetic ploy, by the way
Smearing the name of another scientist with your pseudoscience claims

you should be ashamed of yourself
he might have supported your SCIENCE at one time
but there is NO REASON to assume that he would support your anti-Evolution or other anti-science claims!

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