Cottrell Scholar Awards - 2017
Structural Basis of -1 Programmed Ribosomal Frameshifting in Human T-cell Lymphotropic Virus Type I
In general terms, a virus has just a tiny snippet of genetic material, such as ribonucleic acid – RNA – in comparison with the genetic material in a human cell. But this tiny bit of genetic information is enough to manipulate an unfortunate host cell’s translational machinery – the tools by which proteins are created – to ensure the virus’ successful replication.
Kathryn D. Mouzakis, chemistry, Fort Lewis College, has received a Cottrell Scholar Award from Research Corporation for Science Advancement to improve our understanding of the manipulation process.
Specifically, she is trying to determine the precise microscopic structures involved in “programmed ribosomal frameshifting,” the process by which an RNA virus is thought to interfere with normal protein creation.
Proteins are made by the ribosome, which is a molecular machine found in the cytoplasm of the cell. Ribosomes decode specific messages made of RNA to create unique proteins. Proteins are created by linking specific amino acids, or building blocks, in an order that is directed by the message the ribosome reads. After the messenger RNA, bearing information gleaned from DNA in the cell’s nucleus, passes from the nucleus into the cytoplasm, it is "read" by the ribosome. A polypeptide, or protein, is built according to the instructions in the RNA code, which is deciphered by the ribosome. After the polypeptide is built, it soon folds into a working protein. (The way a protein folds determines its function within the cell.)
Normally, each unique messenger RNA sequence includes the instructions for making a single polypeptide, which the ribosomes decodes by reading from beginning to end. This parallels how the words in a book make up a single novel, which is understood by reading it from the beginning to end. If the order that one read a book was changed, the novel would not make any sense. It is similarly important that when the ribosome reads an RNA, it does not change the order or make a mistake. If it did, the wrong set of amino acids would be linked together and the wrong protein would be made.
Perplexingly, viral RNA genomes often include multiple overlapping messages in a single RNA. These alternate messages code for viral proteins critical to viral replication. However, they can only be accessed by a ribosome if it makes a mistake when reading the RNA – a mistake a ribosome is unlikely to make on its own. If the ribosome were to decode this RNA by following its normal protein creation process, these critical viral proteins would never be made. While good for the host, this is bad for the virus. Successful viral replication depends upon the creation of these proteins.
The viral RNA is thought to trigger a ribosomal mistake that changes how the ribosome reads the RNA – giving it access to the alternate messages coding for critical viral proteins. Mouzakis’ hypothesis is that the viral RNA interferes with how the ribosome reads the RNA at very specific sites and this interference depends upon the 3D shape and sequence of the RNA. She and her colleagues will attempt to define the sequence and shape of these sites by working with the human T-cell lymphotropic virus type 1 RNA genome. HTLV-1 has been implicated in certain spinal cord diseases and as a link to leukemia.
There is also an education component to the Cottrell Scholar Award. Mouzakis will use some of the funding to modify the current research-based advanced biochemistry laboratory course, CHEM 411, at FLC so that it functions as a sustainable chemistry undergraduate research experience. She will use additional funds to establish a four-week transitional lab in the preceding laboratory course, CHEM 312.
“This educational plan will have a substantial impact on undergraduate education at FLC,” she said.