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August 17, 2007 -- A detailed map that pinpoints the location of every atom in a
450-million-yeard-old resurrected protein reveals the precise
evolutionary steps needed to create the molecule's modern version,
according to researchers from the University of North Carolina at
Chapel Hill and the University of Oregon.
now, scientists trying to unravel the evolution of the proteins and
other molecules necessary for life have worked backwards, making
educated guesses based on modern human body chemistry. By moving
forward from an ancient protein, the team laid out the step-by-step
progression required to reach its current form and function.
The study appears in the Aug. 17, 2007, issue of the journal Science.
were able to see exactly how mutations in the ancient structure led to
the modern receptor," said lead author Eric Ortlund, who carried out
the research as a UNC-Chapel Hill postdoctoral fellow. Ortlund is now
an assistant professor of biochemistry in the Emory University School
In the current study, Ortlund and Matt Redinbo, a
professor of chemistry, biochemistry and biophysics at UNC-Chapel Hill,
generated a three-dimensional picture of the ancient receptor with an
imaging technique called X-ray crystallography. The nanoscale image
revealed the receptor's structure, down to the placement of every atom.
With the structure in place, Ortlund and his colleagues retraced
The researchers examined the precursor to a
modern protein known as a glucocorticoid receptor. In humans, the
receptor plays a crucial role, responding to the hormone cortisol and
regulating the body's stress response. The two - receptor and hormone -
fit together as precisely as a lock and key. The precursor preferred a
different hormone, so several mutations were necessary before the lock
could fit the cortisol key.
The University of Oregon team, which
included postdoctoral scientist Jamie Bridgham, resurrected the ancient
protein via a large database of modern receptor genes. This earlier
work, which compared the genetic similarities and differences among two
of these modern genes, found the receptor descended from a single
common genetic ancestor 450 million years ago. The researchers then
recreated the ancient receptor in the laboratory.
mutations were needed to bridge the 450-million-year gulf, the
researchers found. However, not every mutation changed the protein's
function. These "permissive" mutations appear to pave the way for
future, more significant changes. "It's like they prepared for
opportunity to knock in the form of a new hormone," Ortlund said.
permissive mutations bolstered the receptor's structure, like
contractors reinforce a historic home's foundation before making
renovations. After these changes took place, a more extreme mutation
repositioned an entire group of atoms, bringing them closer to fitting
the cortisol hormone. Another created the tight new fit with cortisol.
permissive mutations are chance events. If they hadn't happened first,
then the path to the new function could have become an evolutionary
road not taken," said co-author Joe Thornton, a professor of
evolutionary biology at the University of Oregon.
researchers worked out which mutations came first by synthesizing
different versions of the mutated protein in the laboratory. Had the
radical mutations come first, the receptor protein would have lost its
function entirely, they found.Source : University of North Carolina at Chapel Hill
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