MCB NOTES
SEPTEMBER 2013
Nature makes room for new genes
12 to 15 million years ago a new gene appeared in a fruit
fly. In today’s flies that gene encodes a protein that is essential
for fly viability. But how has it become so essential since, when
it first appeared, fruit flies had been living for millions of years
without that gene? How could that new gene have become
so important? This paradox of how newly evolved genes take
(Left) Chromosomes (blue) are pulled from one
another by spindles (red) during mitosis in a
normal cell. (Right) Without Umbria, mitosis is
abnormal.
on essential functions has now been solved by Prof. Barbara
Mellone, her student Leah Rosin and several US and German
colleagues. They reported how one developmental gene in
fruit flies evolved a new function in the June 7 issue of the journal Science.
Mellone and her co-authors studied a gene called Umbrea. The Umbrea gene
continued on page 2
Viral protein softens up to trick its host
Some viruses use a soft touch to invade their host. Surrounded by a
rigid protein coat to survive in the outside world, these viruses must
“soften” their coats to enter a host cell. How they do this is the subject
of a recent National Institutes of Health award to Prof. Eric May. The
$250,000, 2-year new investigator grant will allow him to conduct a
computer-based examination of how viral coat proteins refold as they
cross into their hosts.
Prof. May will study the Flock House virus (FHV) and Poliovirus. He
currently focuses on the insect virus FHV that uses 2 ribonucleic acids
(RNAs) as its genetic material. A coat or capsid made of a single kind
15 capsid proteins of the Flock
House virus are shown in red, blue
and gray. The membrane active
peptides are in yellow.
of protein surrounds these RNAs. When FHV contacts a host cell, the host surrounds it
MCB Factoid
5 new MCB professors
help make a dent in
instruction demand to
meet rising enrollments
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Prof. Parent begins new faculty position at Michigan State
PhD student DeFalco awarded NSF summer fellowship to
study in Singapore
PhD student Launer-Falty uses travel award to present
poster at RNA meeting in Switzerland
New genes
arose during fly evolution when another gene called HP1B
was duplicated. That made two copies of HP1B, and both,
presumably, had the same function. Over time one copy gained a new function
and became Umbrea. "The new function that is acquired initially is a redundant
function,” Mellone explained, “Eventually the redundant function is lost as the
new gene is getting better and better at the job it is performing."
Natural selection quickly weeds out a gene that serves a duplicated purpose,
so why was Umbrea retained? Mellone and associates were able to trace the
molecular steps that the Umbrea protein took during its evolution that allowed it to take on a new function.
They discovered that a portion of the HP1B-like protein was lost and the remaining portion acquired different
amino acids that allowed it to bind to proteins that HP1B does not bind. Those new protein partners interact
with a different part of the chromosomal DNA (called the centromere) than does HP1B.
The team needed to determine Umbrea’s role in cell development so they relied on Mellone, who has
expertise in cell visualization technologies, to examine cell mitosis. Mitosis is the process that a cell uses to
separate newly made pairs of chromosomes by dragging each pair away from one another by their
centromeres. "We investigated if the localization of this protein had anything to do with the newly acquired
essential function,” Mellone said. "Our job was to look at the different stages of mitosis and centromere
function and determine if this process was affected by the lack of Umbrea." Mellone and Rosin found that
cells lacking Umbrea experienced serious errors in mitosis, consistent with its novel role at centromeres.
What impact do these findings have on medical research? Mellone and her colleagues deliver a caution
for those engaged in gene discovery efforts in medicine. “A lot of gene discovery for human disease occurs
in model organisms and a lot of genes are discarded in those searches because they are nonessential,” she
said. The message of her paper is “don't overlook things that may have acquired new functions in other
organisms.” This research shows that small evolutionary steps can have large functional consequences.
Viral protein changes shape
with a membrane to bring it inside. The cell then floods this
membrane-enclosed compartment with acid to destroy materials inside. The
FHV survives this by changing the shape of its capsid protein to expose a buried
portion of the protein, called a membrane active
peptide, which attaches the virus to the surrounding
membrane. This allows the FHV to escape the acid
by passing through the membrane into the host cell
cytoplasm where its RNAs cause the host cell to
make more viruses.
"Rather than
simulating the full
capsid, we just
simulate a piece
of the capsid."
"That low pH seems to be the trigger for these small peptides to escape from
the interior of the capsid to the exterior,” said May. How each capsid protein undergoes such a dramatic
change of shape is the subject of May’s project. He is using advanced computer simulations of capsid
protein structures to model this process. However, 180 copies of the protein make up the capsid, so
examining them all at the same time is computationally too intensive.
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MCB NOTES September 2013
"Rather than simulating the full capsid, we just simulate a piece of the capsid," May explained. He
examines the movements of a single protein, but includes its interactions with all the copies of the protein
that surround it. This allows the computer to find the movement of the protein that uses the lowest amount of
energy, that is, the most likely movement that causes the membrane active peptide to become exposed.
This work requires sophisticated computations and a large amount of computer time. To date he has
been able to do his work at UConn Engineering's Booth Engineering Center for Advanced Technology. As
the work progresses and becomes more complex, May is now applying for time at national supercomputer
centers. Future work would benefit from enhanced local computer resources.
Prof. May’s background in engineering leads him to consider biotechnological uses for this protein’s
contortionist tricks. This peptide “arm” of the protein undergoes a major movement in response to the
acidification signal, which might be useful for molecular medical devices. May wonders, "If you had this arm
that could respond to a signal, could you attach molecules to that arm that could bind to a cell receptor?"
May’s combination of engineering and molecular computational expertise positions him to make novel
advances in both the science and technology of protein movement.
MORE NOTES
Former Biochemistry PhD student Parent begins faculty position. Kristin Parent, a 2007
Biochemistry PhD graduate from the lab of Prof. Carolyn Teschke, began a position as
Assistant Professor at Michigan State University in the Department of Biochemistry and
Molecular Biology. Prof. Parent uses electron cryo-microscopy in her research to visualize
the first moments of cell infection by a virus.
NSF Fellowship allows Biochemistry PhD student DeFalco to work abroad. Louis DeFalco,
Jr., a Biochemistry Ph.D. student in Prof. Victoria Robinson’s lab, was awarded an NSF
East Asia and Pacific Summer Institute Fellowship for summer 2013. The award supported
his work with Dr. Ganesh Anand at the National University of Singapore studying
changes in the BipA protein in response to binding small molecules.
SB&B grad student Launer-Felty awarded to attend RNA meeting. Katherine Launer-Felty,
PhD student in the Structural Biology and Biophysics program, was awarded a travel
fellowship to attend the Annual Meeting of the RNA Society in Davos, Switzerland June
11-16. She presented a poster there entitled "Inhibition of Protein Kinase R by Adenovirus
Virus-associated RNA I" that described her research in the lab of Prof. James Cole.
Writer: Prof. Kenneth Noll, MCB; [email protected]
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