Ancient enzymes function like nanopistons to unwind RNA

Sep 02, 2012

Molecular biologists at The University of Texas at Austin have solved one of the mysteries of how double-stranded RNA is remodeled inside cells in both their normal and disease states. The discovery may have implications for treating cancer and viruses in humans.

The research, which was published this week in Nature, found that DEAD-box proteins, which are ancient enzymes found in all forms of life, function as recycling "nanopistons." They use to clamp down and pry open , thereby enabling the formation of new structures.

"If you want to couple fuel energy to mechanical work to drive strand separation, this is a very versatile mechanism," said co-author Alan Lambowitz, the Nancy Lee and Perry R. Bass Regents Chair in Molecular Biology in the College of Natural Sciences and Director of the Institute for Cellular and Molecular Biology.

In all cellular organisms RNA () plays a fundamental role in the translation of genetic information into the synthesis of proteins. DEAD-box proteins are the largest family of what are known as " RNA helicases," which unwind RNA.

"It has been known for some time that these enzymes do not function like traditional helicases," said Eckhard Jankowsky, professor of biochemistry at Case Western Reserve University Medical School. "The manuscript now provides the critical information that explains how the unwinding reaction works. It marks a major step towards understanding the for many steps in RNA biology."

Lambowitz said that the basic insight came when Anna Mallam, a post-doctoral researcher in his lab, hypothesized that DEAD-box proteins function modularly. One area on the protein binds to an ATP molecule, which is the energy source. Another area binds to the double-stranded RNA.

"Once the second domain is latched on to the RNA," said Mallam, "and the first has got its ATP, the 'piston' comes down. It has a sharp edge that drives between the two strands and also grabs on one strand and bends it out of the way."

Lambowitz, Mallam and their colleagues uncovered this mechanism in Mss116p, a DEAD-box protein in yeast. The mechanism is almost certainly universal to the entire family of the proteins, however, and therefore to all domains of life.

"Every DEAD-box protein that we know about has the same structure," said Lambowitz, "and they all presumably use the same mechanism."

Lambowitz said that the Mss116p proteins are particularly useful as a universal remodeling device because they can bind to any RNA.

"It recognizes the geometry of double-stranded RNA," he said. "It doesn't care about the sequence, and doesn't care about what it that particular RNA molecule's function is. It just sees it and binds and for that reason can be incorporated into many different cellular processes."

This flexibility of DEAD-box proteins is essential to the functioning of healthy cells, which rely on a range of molecules for basic processes, including synthesis.

It's also hijacked in cancers, where over-expression of DEAD-box proteins may help drive uncontrolled cell proliferation, and in infections caused by bacteria, fungi, and viruses, which rely on specific DEAD-box proteins for their propagation.

"This is basic science," said Lambowitz. "Its major significance is in understanding, at the root, how this mechanism works. But when you understand how DEAD-box proteins function both in normal cellular processes and in disease processes, you can absolutely begin to think about how they might be targeted in things like cancer and viruses."

"You can even envision, in the far future, how they be incorporated into artificial nanomachines, for switches and other mechanical devices inside and outside the cell."

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irjsiq
1 / 5 (6) Sep 02, 2012
How do these 'DEAD-box proteins' KNOW how to do this?
My Hypothesis being: Knowledge in some form(s) exists Ubiquitously throughout the Universe, and further, I believe 'Thought preceded Matter!' I have no proof of the existence of God; but I have no greater Proof that God does not exist!
Humans have much to discover about 'knowledge', 'thought', 'information'! Perhaps 'Instinct' can provide answers, if we ever unravel the 'wonder of Instinct'! We fob-off esoteric behavior(s), as simply 'Instinctual' and endemic to creatures. Except that the multitudes of aspects of Instinct are incredibly diverse!
There is a very deep pool of awareness/cognizance of which we are yet to investigate and/or discover/study!

Roy J Stewart,
Phoenix AZ
Torbjorn_Larsson_OM
5 / 5 (1) Sep 02, 2012
These nucleotide agnostic enzymes are interesting, because they can derive from the RNA world.

# Creationists shouldn't comment on science, it is hilarious to see.

Biologists discovered nearly 200 years ago that traits are acquired by selection, i.e. the populations learn this by way of heredity. And when the genome was discovered, they knew where the learned information was stored.

This is well understood by science.
Telekinetic
1 / 5 (2) Sep 02, 2012
"There is a very deep pool of awareness/cognizance of which we are yet to investigate and/or discover/study!"- Roy Stewart

I would say that would come under the heading of "consciousness". In this age of astounding revelations in quantum physics, i.e., parallel universes, quantum entanglement, etc., there IS much to be learned. I've often wondered whether there exists in the smallest microbe, virus, and DNA strand a presence that we claim to be exclusively ours. Doesn't a virus replicate itself to guarantee its survival in clever ways like injecting its DNA into a host cell, much like people have done when they colonize the lands of others? And the repair mechanisms of the DNA strand- acting like efficient sentinels sniffing out the mutated, errant code, snipping them out and replacing with corrected ones millions of times, and almost always perfectly in a healthy organism. It is quite amazing, and may not have required a super being, perhaps just a lot of time and "consciousness".
twistlogic
1 / 5 (2) Sep 02, 2012
Torbjorn,

I don't see any evidence that Roy smokes creationism. Methinks it is pot.

Yes, this is very likely a vestige of the RNA world, a world whose only extant fossils are found in the physiologies and genomes of the descendants.

Roy,

Yes, the world is a place of awe, the study of it should fill you with a spiritual joy because the world is wonderful in its intricate simplicities. But ascribing instinct, cognition, volition, etc to tiny molecular machines, is a dead-end pot reverie that explains zip & adds only confusion. Before a scientific theory of conception was devised, armchair "thinkers" offered Preformationism ...sidestepping true explanation by presupposing that the child preexists as a "homunculus" within the sperm. Problem: each homunculus requires even smaller sperm, with even smaller homunculi inside... these homunculi, yet smaller sperm ... ad infinitum. Infinite regression and incoherence plagues non-explanations

Modern biology answered with MECHANISM.
KomMaelstrom
1 / 5 (2) Sep 02, 2012
How do these 'DEAD-box proteins' KNOW how to do this?
My Hypothesis being: Knowledge in some form(s) exists Ubiquitously throughout the Universe, and further, I believe 'Thought preceded Matter!' I have no proof of the existence of God; but I have no greater Proof that God does not exist!
Humans have much to discover about 'knowledge', 'thought', 'information'! Perhaps 'Instinct' can provide answers, if we ever unravel the 'wonder of Instinct'! We fob-off esoteric behavior(s), as simply 'Instinctual' and endemic to creatures. Except that the multitudes of aspects of Instinct are incredibly diverse!
There is a very deep pool of awareness/cognizance of which we are yet to investigate and/or discover/study!

Roy J Stewart,
Phoenix AZ

Come on... Phoenix, too? ;'(
ekim
5 / 5 (3) Sep 03, 2012
How does salt "know" to dissolve in water?
How does the Earth "know" to revolve around the sun?
How does a knife "know" how to cut bread?
I can't "prove" there isn't an invisible monster under my bed.
Sounds very childish when phrased like that.
Torbjorn_Larsson_OM
not rated yet Sep 03, 2012
twistlogic, possibly, I too noticed the fuzzy ambient. =D Pot dualism is effectively creationism as soon as it removes natural mechanisms for something else (eg "KNOW"), so I was pointing that out. Your approach is more direct.

Actually I found a nice read on helicases because this article prompted me, I hadn't noted them before and it had slipped my mind that the ribosome works as one. It starts out with dual strand separation as a problem for the RNA world, and ends up with the ribosome and the genetic code as byproducts!

With a lot of handwaving, I haven't read the details yet, but it is apparent it is a pathway. It is tying the RNA world to the RNA/protein world outside of the mainstream hypothesis of a metabolic tie (with 1-2 aas starting out as coenzymes), and it points to a forcing.

Directed separation had to happen and the translation ratchet does that AFAIU. [ http://www.spring...text.pdf ] Another test for the RNA world.