When it comes to new diagnostics and treatments for cancer, researchers across the world are gaining traction. Now, scientists at Arizona State University's Biodesign Center for Applied Structural Discovery (CASD) are turning to outer space to understand the inner workings of a cancer-linked protein known as Taspase 1.
In conjunction with NASA and the National Cancer Institute, the CASD team plans to grow crystals under the conditions of microgravity within low earth orbit. The ultimate goal is to use this method to prepare proteins for analysis that offer specific targets for new, biologically based drugs that fight cancer with fewer side effects. If successful, this approach will offer a new way to understand proteins that are notoriously resistant to crystallography and other standard methods of structural analysis.
Biochemist Jose Martin Garcia spends his time analyzing protein crystals. Currently, Garcia is leading a collaborative effort with NASA to study how protein crystals form in a microgravity environment. Garcia, SMS doctoral student Nirupa Nagaratnam and undergraduate Rebecca Jernigan and CASD center Director Petra Fromme, Regents' Professor at the School of Molecular Sciences plan to travel to Cape Canaveral on Merritt Island, Florida, in late April to prepare the samples for NASA’s next launch. The cargo ship, SpaceX Falcon 9, will take off on April 30, carrying Taspase 1.
A target for halting the lethal consequences of cancer
Taspase 1 (Tasp 1) is known for its role in developing organs in the human embryo. Glioblastoma brain cancer, breast cancer and some forms of leukemia are able to hijack Taspase 1 to rapidly increase the population of cancerous cells. Glioblastoma brain cancer is considered incurable because the cells are able to reproduce so quickly that doctors are unable to stop the process. These tumors can be removed but it does not rid the brain of the residual cancer cells that continue to aggressively multiply. This was the case for Sen. John McCain, who passed away one year after his diagnosis and full tumor removal.
Tasp 1 permanently changes the proteins that control the DNA, called histones. In this circumstance, cancer cells multiply more readily without interference. This irreversible process is called nononcogenic gene addiction. Tasp 1 serves as a promising target for cancer therapy since its absence slows the cancerous cell cycle, triggers cancer cell death and stops other enzymes from aiding in Tasp 1’s destructive potential. Halting Tasp 1 would lead to eradicating tumor cells without destroying surrounding tissue.
“Since proteins are the atomic managers of all aspects of a living cell, understanding the structures is imperative to understanding our own health,” Garcia said.
Scientists often turn to protein crystallography to determine these structures, in which ultra-fast X-rays are taken of intricately formed crystals.
Stacking sticky proteins
Protein crystallography is a tricky business, or better put, a sticky business. It can take decades to understand the structure of a protein. This is often due to the tedious process involved with the formation of the crystals themselves. Protein crystals form by stacking one protein atop the next, atop the next, atop the next etc., until enough proteins are present to adequately produce a pattern from the X-ray.
If the proteins are not sticky enough, they won’t stack. If they are too sticky, they won’t stack evenly. The process has to be just right or the X-ray diffraction patterns will not separate out enough to identify the atomic parts hidden within them. The goal is to achieve a high resolution where the spots on a diffraction pattern are distinct; then researchers can accurately observe and understand which amino acids are located within a given space. If the crystals do not grow in an organized fashion, the diffraction patterns will overlap and the atomic components within that area of the protein cannot be resolved.
Capturing Taspase 1 with X-ray vision
X-ray crystallography is the most common method used to see the three-dimensional structure of a protein. In crystallography, X-rays are shot through protein crystals to create a visual pattern on a detector. With that pattern, scientists are able to perform some complicated mathematics to indicate the actual amino acids and chemistry within the protein.
“Knowing Tasp 1’s exact atomic composition, we can much more easily design an appropriate inhibitor, and perhaps, accelerate pharmaceutical research to discover new ways to intervene in the growth of cancer,” states Garcia.
With microgravity, the pressure is off
What does outer space offer to a crystal that cannot be achieved on the earth? The answer is microgravity. Gravity, of course, keeps us grounded here on earth, but can be an impediment to a well-formed protein crystal in the field of crystallography.
Some proteins are easier than others to extract from cells and crystallize. One major setback occurs when the protein structure is not symmetrical. Tasp 1’s structure has eluded experts in the past, who were only able to determine truncated portions of the protein or speculate about the structure with computer simulation modeling. Garcia and his team are the first to publish the full-length, three-dimensional shape of the protein, but not at the resolution level that they would like.
Tasp 1 does not readily cooperate with the crystal stacking process due to the complexity of its shape and structure. The protein has three coiled sections (alpha helixes) that protrude vertically from top and bottom of the central stack of dihexameric rings. As the crystal forms, these protrusions are not rigid enough to stack in an organized fashion, and this is the crux of the resolution problem.
These pesky outshoots are directly involved with the activity of the protein, making them prime areas of interest for drug design. If the alpha helices do not stack evenly, higher resolutions cannot be achieved.
Garcia and his team believe that a microgravity environment may offer the answer. In a decreased gravity environment, the flexible portions of the protein are expected to line up properly, forming the ideal crystal to analyze.
According to NASA, “space is an excellent environment to study complex, three-dimensional proteins, because gravity and convective forces do not get in the way of crystal formation, which allows creation of larger and more perfect crystals. With large crystals, scientists on the ground can use X-ray crystallography to determine how the protein is organized. Determining protein structures helps researchers design new drugs.”
Written by Christine Lewis
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