Advance Toward Nanotechy Approach To Protein Engineering Reported By UCLA Physic

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Advance Toward Nanotechy Approach To Protein Engineering Reported By

UCLA Physicists

http://www.medicalnewstoday.com/medicalnews.php?newsid=45012

UCLA physicists report a significant step toward a new approach to

protein engineering in the June online edition, and in the July print

issue, of the Journal of the American Chemical Society.

" We are learning to control proteins in a new way, " said Giovanni

Zocchi, UCLA associate professor of physics and co-author of the

study. Zocchi said the new approach could lead ultimately to " smart

medicines that can be controlled " and could have reduced side

effects. Mimicking one essential cellular control mechanism, Zocchi's

laboratory has completed an important preliminary step.

Zocchi and UCLA physics graduate student Choi report one

representative example where the chemical mechanism by which the cell

controls the function of its proteins can be effectively replaced, in

vitro, by mechanical control. Specifically, they show how an enzyme

complex called Protein Kinase A (PKA) -- which plays a fundamental

role in the cell's signaling and metabolic pathways, and is

controlled in the cell by a ubiquitous messenger molecule called

cyclic AMP -- can instead be controlled mechanically by a nanodevice

that the researchers attached to the enzyme complex. The nanodevice

is essentially a molecular spring made of DNA.

" Molecular biologists have been trained for 50 years to think that

because the sequence of amino acids determines a protein's structure

and the structure determines its function, if you want to change the

structure, the way to do so is to change the sequence of amino acids.

While that approach is correct, it is not the only way. We are

introducing the notion that you can keep the sequence but change the

structure with mechanical forces.

" This research has many ramifications, and may lead to a better

fundamental understanding, as well as new directions for

biotechnology and perhaps new approaches to medical treatments. "

PKA, a complex of four protein molecules, contains two regulatory

subunits and two catalytic subunits. Zocchi and Choi mechanically

activated PKA by placing a controlled mechanical stress on two

specific points in the regulatory subunit, which causes that subunit

to fall off from the catalytic subunit, activating the enzyme.

In order to obtain the desired effect, the mechanical tension is

applied at specific locations in the regulatory subunit, Choi said.

Knowing those locations requires a detailed understanding of the

structure of the enzyme.

The research was federally funded by the National Science Foundation.

Proteins, the molecular machines that perform all tasks in the living

cell, are switched on and off in living cells by a mechanism called

allosteric control; proteins are regulated by other molecules that

bind to their surface, inducing a change of conformation, or

distortion in the shape, of the protein, making the protein either

active or inactive, Zocchi explained.

Cyclic AMP (cAMP) binds to PKA's regulatory subunit and induces a

change of conformation that leads to the catalytic subunit's

detaching from the regulatory subunit; this separation of the two

subunits is how the enzyme complex is turned on in the cell, Zocchi

said.

" We can activate the enzyme mechanically, while leaving intact the

natural activation mechanism by cAMP, " said Zocchi, a member of the

California NanoSystems Institute. " We believe this approach to

protein control can be applied to virtually any protein or protein

complex. "

Zocchi's group first demonstrated mechanical control of protein

conformation last year, when the physicists attached a controllable

molecular spring, made of a short piece of DNA, to a protein and used

it to inhibit its function. In the new research, the group succeeded

in activating the enzyme PKA through the same principle, by using the

molecular spring to induce the change in conformation that, in the

cell, is induced by the natural activator of PKA (the signaling

molecule cAMP).

Zocchi's group can mimic with mechanical tension the natural

allosteric mechanism by which PKA is regulated by cAMP. PKA is

significantly more complex than the protein that Zocchi's group used

last year.

What are Zocchi's future research plans?

" I want to see whether we can make molecules which kill a cell based

on the genetic signature of the cell, " Zocchi said. " Cancer cells

would be an obvious application. This will however require many

further steps. So far, we have only worked in vitro. The exciting

part is, from the outside, cancer cells can look like normal cells,

but inside they carry a genetic mark.

" In the future, perhaps we can control more complicated molecular

machines such as ribosomes. Many antibiotics work by blocking the

ribosome of bacteria. "

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