Science Discovers a Key Protein in Aging, Cancer
UCLA biochemists have mapped the structure of a key proteinRNA required for the assembly of telomerase, an enzyme important in both cancer and aging
The genetic code of both the single-celled protozoanTetrahymena and humans is stored within long strands of DNA folded neatly within each animals' chromosomes.
The telomerase enzyme helps create telomeres protective caps at the ends of each chromosome that prevent the degeneration of our DNA, according to Juli Feigon, UCLA professor of chemistry, biochemistry and senior author of the study.
Her and her collaborators' results were published June 14 in the online edition of the journal Molecular Cell and are scheduled for publication in the print edition on July 13, 2012.
Each time a cell divides telomeres shorten, acting like the slow-burning fuse of a time bomb. After many divisions, the telomeres become eroded to a point that can trigger cell death.
Cells with abnormally high levels of active telomerase, constantly rebuild their protective chromosomal caps, allowing them to replicate indefinitely and become, essentially, immortal. Yet undying cells generally prove to be more of a curse than a blessing, Feigon says.
"Telomerase is not very active in most of our cells because we don't want them to live forever," said Feigon, who is also a researcher at UCLA's Molecular Biology Institute and a member of the National Academy of Sciences. "After many generations, DNA damage builds up and we wouldn't want to pass those errors on to subsequent cells."
Overactive telomerase has potentially lethal consequences far beyond immortalizing error riddled DNA. The enzyme is particularly lively within cancer cells, preventing them from dying off as well. Finding a way to turn off telomerase in cancer cells might help prevent the diseased cells from multiplying.
But, flipping the switch on telomerase could mean stopping it from forming in the first place, says Feigon.
Feigon: "Any time you want to stop an enzyme, you can target activity, but you can also target assembly. If you keep it from assembling, that's just as good as keeping it from being active, because it never even forms."
While there is enormous interest in telomerase because of its connection to cancer and aging, very little is known about its three-dimensional structure or how it is formed, says Feigon.
Four years ago, UCLA postdoctoral scholar Mahavir Singh set out to determine how a strand of RNA and multiple proteins bind together to form telomerase. He set his sights on the p65 protein, one of the key components of telomerase. Like many proteins, p65 is a long chain of both stiff and flexible links that fold in upon each another in a preset pattern. At the very end of the p65 protein is a floppy, disordered tail.
"We knew the tail was important for the protein's function, but it wasn't clear how or why," said Singh, first author of the current study. "From the structure, it became evident how it interacts with the telomerase RNA."
When Singh snipped off the flexible tail from p65, he found the assembly of telomerase became severely limited. The tailless p65 simply couldn't pull together the telomerase enzyme.
Upon assembly, the flexible tail of p65 transforms
into a rigid crowbar that pries apart the
strands of the RNA double helix.
Using both X-ray crystallography and nuclear magnetic resonance spectroscopy, Singh probed the structure of the protein during its interaction with telomerase RNA. He found that upon meeting, the flexible tail transforms into a rigid crowbar that pries apart the strands of the RNA double helix. The newly altered protein tail bends the RNA into a new shape required to bind a protein called TERT (telomerase reverse transcriptase) to telomerase, .
The p65 protein not only brings two parts of the RNA closer together allowing for the attachment of TERT, but it also folds around the end of the RNA strands protecting them during assembly. Without this protein shield, "naked" RNA is susceptible to being chewed up by other enzymes, says Singh.
The p65 protein belongs to a family of "La-motif" proteins, molecules that act as "RNA chaperones" in many organisms including humans, says Feigon.
Feigon: "How the p65 protein binds with RNA has never been clear. Nobody could figure it out, and that's partly because they were missing a critical, extra part of the protein which changes from being a completely random coil to being folded and ordered when it interacts with RNA."
Studying p65 within the humble Tetrahymena may help Singh and Feigon better understand its La-motif cousins within the human body, which also have protein tails.
Feigon: "A lot of data indicates that the protein tail is important for the binding of all kinds of RNAs in human cells. It is particularly critical for the translation of the hepatitis C viral RNA. Now we can potentially predict how those proteins will assemble and interact with their RNAs."
The researchers who first discovered telomerase and were awarded the Nobel Prize in 2009, also used Tetrahymena thermophila in their research.
This research was federally funded by the National Science Foundation and the National Institutes of Health. Other co-authors included UCLA senior staff scientist Duilio Cascio, UCLA postdoctoral scholars Zhongua Wang and Bon-Kyung Koo, UCLA undergraduate researcher Anooj Patel, and UC Berkeley professor of molecular and cell biology Kathleen Collins.
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Original article: http://newsroom.ucla.edu/portal/ucla/ucla-biochemists-identify-a-mechanism-235159.aspx