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.
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 chemical energy to clamp down and
pry open RNA strands, thereby enabling the formation of new structures.
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.
all cellular organisms RNA (ribonucleic acid) 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.
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 molecular mechanics for many steps in RNA biology.”
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.
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.”
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.
DEAD-box protein that we know about has the same structure,” said
Lambowitz, “and they all presumably use the same mechanism.”
said that the Mss116p proteins are particularly useful as a universal
remodeling device because they can bind to any RNA.
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.”
flexibility of DEAD-box proteins is essential to the functioning of
healthy cells, which rely on a range of RNA molecules for basic
processes, including protein synthesis.
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.
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.”
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.”
Structural basis for RNA-duplex recognition and unwinding by the DEAD-box helicase Mss116p
Source: University of Texas at Austin