Researcher of the Month: Natalia Jura, PhD

Posted: February 18, 2020
By Shelley Wong

Natalia Jura, PhD, is an associate professor in the Cardiovascular Research Institute and the Department of Cellular and Molecular Pharmacology. Her lab is focused on understanding how cells transmit extracellular signals across the membrane via a class of membrane-embedded proteins called Receptor Tyrosine Kinases. At the core of her research is a family of human epidermal growth factor receptor (HERs), which are important targets in breast and lung cancers.

Jura uses a model of Sutro Tower in her office as a “local example” of the receptors, though her work is concerned with how signals are received, rather than transmitted. She compares protein molecules on the surface of cells to antennae: receptors receive signals along the plasma membrane, allowing them to sense what is on the outside to transmit information to the inside of the cell. This initiates signaling responses, telling cells to start or stop dividing, or to move, actions which create tissue and organs and maintain them in homeostatic balance throughout life.

Jura and colleagues are focused on understanding how cancer disrupts balance in cellular communication by altering the function of Receptor Tyrosine Kinases. In cancer, receptors often fire up without seeing extracellular signals or are unable to stop signaling when activated due to mutations or other genetic alterations that change the structure of the receptors.

“We are trying to understand how these aberrations work at the level of HER receptor machinery. We are a structural biology lab, so we are solving three-dimensional structures of proteins at atomic resolution,” says Jura.

But first, it is crucial to understand how receptors work in normal cells. To date, no one has described the structure of an intact active HER receptor complex to explain how conformational changes in the receptor modules facing the outside and inside of the cell are coupled across the membrane to turn the receptors on. Progress has been limited by production of sufficient material for structural studies. “Receptors are inherently unstable and cells do not make many of these molecules because it is toxic for them,” says Jura. She is excited to report progress in the purification of these molecules as one unit, which has been a technical challenge.

Traditionally, researchers have used X-ray crystallography to obtain structures of receptor fragments, but this relies on the protein to form a crystal. However, intact receptors are unlikely to crystallize. “Crystallization is challenging when a protein is larger and can adopt different states because it has too much flexibility,” says Jura. “We are using cryogenic electron microscopy (cryo-EM) to tackle the structure of these full-length proteins. These are the first studies that will allow us to look at these molecules as a whole piece, understand their architecture, and see how mutations change them.”

Cryo-EM allows researchers to obtain high-resolution structures of proteins in solution, which is closer to their native environment. It does not rely on proteins to form crystals and allows researchers to identify a higher spectrum of protein conformations in one sample. This is a great advantage. “By nature, signaling proteins adopt different conformational states to convey a message. Capturing these states is an inherent challenge for structural biology. Cryo-EM offers glimpses into these different states much more often than crystallography,” says Jura.

Her work using cryo-EM is in close collaboration with QBI fellow Kliment Verba, PhD. Verba is an expert in the application of cryo-EM to the studies of multi-protein signaling complexes, due to experience he gained as a graduate student with David Agard, PhD. Jura cites Agard and Yifan Cheng, PhD, for their cryo-EM technological advances that started a “resolution revolution,” opening doors to using cryo-EM for the studies of proteins as challenging as HER receptors. The most recent is the creation of EM “smart” grids to improve conditions for freezing proteins and limiting their isolation time. With these advances and the uniquely collaborative spirit of UCSF, Jura is building momentum in her work.

“We’re taking high-resolution snapshots of these important signaling complexes for fundamental knowledge and discovery, but also for clinical gain in cancer, which targets these receptors. We hope that our research will help others think of completely new ways of targeting these complexes,” says Jura.

“UCSF is an unusual community where the departments don’t matter in the flow of scientific expertise and knowledge. People here team up very quickly based on their interest, and it is extremely easy to collaborate. There is also a great willingness and generosity of the structural biology community here at UCSF to make new technologies available and train people.”

Growing up in Poland, Jura had scientist parents (an engineer father and a pharmacist mother), so science was “always in the air.” She became even more enthusiastic about the subject due to the “contagious” enthusiasm of her elementary school chemistry teacher and the example of her grandmother who, remarkably for the 1940s, earned her university degree in pharmacy after the birth of two daughters.

Jura remembers being inspired by visits to her grandmother’s pharmacy. “I remember a wall of reagents and seeing her mix medicines and use scales – and the smell. I was always fascinated by the chemistry component.”

She is now passing on her scientific enthusiasm by mentoring the next generation. Her advice? “You have to work on something that you are truly interested in, on a question that you want to answer. Science is full of great mysteries, but some mysteries speak to us more than others. It's almost like a match – can you find something that guides you? This helps because training periods can be sometimes difficult. It takes a while before the mysteries are unlocked. And always keep your mind open to refining your original hypothesis. The scientific journey is most rewarding when it is unexpected.”

Looking ahead, Jura is inspired and feels fortunate to be part of UCSF’s research community. She says, “We are living in amazing times right now. Being a part of a community where so many new and important discoveries take place all the time is a privilege and I hope I can continue this work as long as possible.”