Rehydrate -- Your RNA Needs It

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Rehydrate -- Your RNA Needs It

http://www.medicalnewstoday.com/medicalnews.php?newsid=50309

Water, that molecule-of-all-trades, is famous for its roles in

shaping the Earth, sustaining living creatures and serving as a

universal solvent.

Now, researchers at the University of Michigan and the Academy of

Sciences of the Czech Republic have uncovered two previously unknown

roles for water in RNA enzymes, molecules which themselves play

critical roles in living cells and show promising medical

applications.

The researchers' findings will be published online in the Proceedings

of the National Academy of Sciences (PNAS) this week.

RNA enzymes, also known as ribozymes, accelerate chemical reactions

inside cells, just as their better-known protein counterparts do. And

just as a protein enzyme is not a static structure, a ribozyme also

changes shape, cycling back and forth between active and inactive

forms (called conformations).

In earlier work, a team led by U-M's Nils Walter, associate professor

of chemistry, found that modifications made anywhere on the ribozyme

molecule---even far from the site where the chemical reaction occurs--

-affect the rates at which the enzyme changes conformation and

catalyzes the reaction. Something similar had been seen in protein

enzymes, but never before in RNA enzymes.

The earlier finding, published in PNAS two years ago, suggested that

information about changes in distant parts of the ribozyme travels

through some sort of network to the core of the molecule, where

chemical reactions take place. The latest work shows that water

molecules trapped inside the ribozyme's core are essential components

of that network.

The network acts like a jostling crowd at a cocktail party, where

hydrogen bonds---weak, electrostatic attractions between molecules or

parts of molecules---take the place of handshakes. Water molecules

trapped in ribozymes can form hydrogen bonds with other water

molecules or with parts of the ribozyme molecule.

" The way we interpret the data is that in ribozymes, a chemical

modification introduced at one place changes the local structure

slightly, " Walter said. The building blocks making up the ribozyme

wiggle into different positions and in the process must let go of

some hydrogen bonds and form others, just as partygoers shift

position and engage with other guests.

" As a consequence, their hydrogen bonding partners---some of which

are water molecules---also rearrange. Then their hydrogen bonding

partners also rearrange, creating a domino effect, where a local

modification spreads throughout the molecule and modifies the

structure elsewhere, even at quite a distance, " Walter said. Water

facilitates the process by increasing the number of hydrogen bonds

and making the ribozyme behave as an interconnected whole.

Walter and coworkers also found evidence that water is directly

involved in catalyzing reactions in the ribozyme's core, another

previously unknown role. The research team explored the new roles of

water molecules using a combination of computational simulations and

a technique called single-molecule fluorescence resonance energy

transfer (FRET), which allowed the researchers to directly observe

and measure how quickly the ribozyme switched forms and how the rates

changed when various parts of the molecule were altered.

The situation in ribozymes contrasts with what happens in protein

enzymes, which repel water from their cores and rely on direct

contact, rather than a network of hydrogen bonds, to communicate

structural changes from one part of the molecule to another.

So far, the researchers have focused on one particular ribozyme, but

Walter predicts the findings will apply to other RNAs. If so, those

findings should be of great interest to scientists who are learning

more all the time about the diverse roles of RNA. Once thought to be

only a passive carrier of encoded genetic information, RNA is now

known to regulate gene expression and other important cellular

processes and to act as a sort of sensor---detecting cellular signals

and carrying out appropriate reactions in response. In fact, there

are many more so-called non-protein coding RNAs in the cell (around

100,000 in humans), which are not translated into protein, than there

are protein coding messenger RNAs (about 25,000), making these vast

numbers of RNA molecules central players in our bodies.

Work is also underway in academic and industrial labs around the

world to engineer RNA for medical purposes. The engineered molecules,

called RNA aptamers, are selected for their ability to bind to

particular proteins involved in certain diseases, blocking key steps

in the disease process.

" It's likely that water helps mediate the binding between these

aptamers and their disease-causing protein targets, ultimately

keeping the protein away from where it can wreak havoc, " Walter

said. " So the fundamental understanding we are gaining of the role of

water in RNA almost certainly will have relevance in the treatment or

prevention of disease. "