Defying Gravity: SLU Scientists Seek Elusive Answers in Space
Can Microgravity Provide Clear Pictures of Important Proteins’ Molecular Structures?
|Saint Louis University research hitched a ride to NASA's International Space Station U.S. National Laboratory on the recent SpaceX Dragon capsule. Photo courtesy SpaceX|
ST. LOUIS – Saint Louis University research hitched a ride to NASA’s International Space Station U.S. National Laboratory on the recent SpaceX Dragon capsule, thanks to last year’s $267,000 grant from the Center for the Advancement of Science in Space (CASIS). Researchers Sergey Korolev, Ph.D., and Enrico Di Cera, M.D., sent their work into space to try to solve two difficult problems and they believe the answers could lead to better therapies in several areas of medicine.
Korolev and Di Cera work on obtaining “snap shots” of protein structures through x-ray crystallography. They grow crystals of the protein they want to study, shoot x-rays at them and record data about the way the rays are scattered by crystals. Then they use computer programs to create an image of the protein based on that data.
Once scientists can visualize the three dimensional structure of a molecule, they can begin to piece together the way in which the protein functions and interacts with other molecules in the body, or drugs, shedding light on the underpinnings and pharmacological control of processes like blood clotting or inflammation.
One of the most challenging parts of this process is the first step: growing the protein crystals in the first place.
“The main challenge is in getting the crystals,” said Korolev, who is associate professor of biochemistry and molecular biology at SLU.
“Solving the molecular structure of a protein is the ultimate information, and it is so difficult,” Korolev said. “Proteins are the worst molecules for this. They are huge; sometimes they are made up of tens of thousands of atoms, flexible, and are not well suited to form a well ordered crystal of sufficient quality and size. We can spend years trying to crystalize a specific protein using thousands of different chemicals. It requires lots of work and money and any new way to improve crystallization is under high demand.
Crystal growth takes several weeks or even months. Under normal gravity, the solvent around the forming crystals may become depleted of protein and the crystal doesn’t grow properly. Even if they form, crystals may not be uniform.
About a decade ago, scientists began sending their work to space to grow the crystals under a different condition – microgravity – and they’ve had some success with the process. CASIS, the Center for the Advancement of Science in Space, which was chosen in 2011 by NASA to be the sole manager of the International Space Station U.S. National Laboratory, has designated crystal structure work in microgravity as one of their key areas of focus.
Several proteins of interest to Korolev and Di Cera had been crystallized using traditional methods but the quality was insufficient to obtain high resolution structures. The scientists sent their research to the International Space Station in the hopes of growing larger and better quality crystals.
Sergey Korolev, Ph.D., and Phospholipase A2
Korolev is hoping to crystalize calcium-independent phospholipase A2, an important enzyme involved in many different cell processes. In fact, phospholipase 2 appears to play so many roles – including involvement in the inflammation process, cardiac processes, and in calcium signaling – that scientists have trouble sorting out how it interacts with other proteins in each pathway. While initially protective, it ultimately can damage tissues and mutants of this product are associated with early onset Parkinson’s disease.
“The problem with this protein is that it has multiple domains. It’s a multi-task enzyme. It’s involved in many different processes, and the field isn’t moving forward because it’s difficult to uncouple these processes,” Korolev said.
“If we know the atomic structure, we can try to predict how it gets activated and how it interacts with other molecules. It could bring the whole field of study to a new level of understanding.”
Enrico Di Cera, M.D., and Prothrombin
Di Cera, M.D., who is chair of the Edward A. Doisy department of biochemistry and molecular biology at SLU, aims to develop a better understanding of the structure of prothrombin, the physiological precursor of thrombin, a key vitamin K-dependent blood-clotting protein.
Blood clotting performs the important function of stopping blood loss after an injury. However, when triggered in the wrong conditions, clotting can lead to debilitating or fatal conditions such as a heart attack, stroke or deep vein thrombosis.
Before thrombin becomes active, it circulates throughout the blood in the inactive zymogen form prothrombin. When the active enzyme is needed (after a vascular injury, for example), the coagulation cascade is initiated and prothrombin is converted into an active enzyme that causes blood to clot.
By refining our understanding of prothrombin’s structure, Di Cera hopes to define the mechanism of activation and find new approaches to developing medications to manage blood clotting.
Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.
About CASIS: The Center for the Advancement of Science in Space (CASIS) was selected by NASA in July 2011 to maximize use of the International Space Station (ISS) U.S. National Laboratory through 2020. CASIS is dedicated to supporting and accelerating innovations and new discoveries that will enhance the health and wellbeing of people and our planet. For more information, visit www.iss-casis.org.
About the ISS National Laboratory: In 2005, Congress designated the U.S. portion of the International Space Station as the nation's newest national laboratory to maximize its use for improving life on Earth, promoting collaboration among diverse users, and advancing STEM education. This unique laboratory environment is available for use by other U.S. government agencies and by academic and private institutions, providing access to the permanent microgravity setting, vantage point in low Earth orbit, and varied environments of space.