Structure of the tTRBD–TBE complex
Over-activation of telomerase in 90% of malignant tumors has made the unusual enzyme a prime target for drug development efforts. Researchers at UC Santa Cruz have determined the structure of a key part of the enzyme telomerase, which is active in most cancers and enables cancer cells to proliferate indefinitely. They reveal how the enzyme carries out a crucial function involved in protecting the ends of chromosomes.
Repetitive DNA sequences at the ends of chromosomes, called telomeres, serve as protective caps. As cells divide, their telomeres get progressively shorter, until eventually the cells stop dividing. The telomerase enzyme lengthens telomeres by adding more of the repetitive DNA sequence. It is active in cells that need to keep dividing indefinitely, such as stem cells, and in about 90 percent of malignant tumors.
Telomerase is an unusual enzyme in that it is composed of a protein and RNA component. The protein is a reverse transcriptase, which makes DNA copies of RNA sequences. The RNA component provides the template that the enzyme copies to generate the telomere DNA sequence.
“The template is the track that the enzyme train runs along, and what’s so unique with telomerase is that the track is an integral component of the enzyme itself,” Stone said.
The enzyme copies the same short segment of RNA template over and over again to generate the repetitive DNA of the telomere. One of the mysteries has been how the copied sequence is so precisely defined, since it is a relatively small segment of the much larger telomerase RNA. Stone’s group solved the structure of a region called the RNA binding domain, and their findings explain how the boundary of the template is defined by the interplay between protein and RNA components of the telomerase.
T. thermophila telomerase composition and catalytic cycle.
MOA: the binding domain tethers one end of the RNA so that only a defined sequence can move through the active site of the enzyme where copying takes place. As the enzyme copies the template sequence, it pulls the RNA through the active site until there is no more slack left, at which point a molecular “tug of war” between binding domain and reverse transcriptase stops movement of RNA into the active site.
“The reverse transcriptase is pulling on the RNA, but the structural resistance of the RNA binding domain prohibits the movement of more RNA, and that’s how the template boundary is defined,” Stone said.
The enzyme then resets to the beginning of the template sequence and starts over. The section of RNA that is tethered to the protein forms a RNA stem loop, and a protein structure in the binding domain is wedged into the base of the RNA stem, anchoring it in place. http://news.ucsc.edu/2015/10/telomerase.html
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