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By Lesley Snyder
Understanding the Language of Cells
The biochemists and structural biologists in the Jura Lab, which is affiliated with the Cardiovascular Research Institute (CVRI) and the UCSF Department of Cellular and Molecular Pharmacology, seek to understand what regulates how cells compute signals received from other cells or the environment to control cell growth and survival.
The lab, led by Natalia Jura, PhD, looks at how cells grow when they are healthy, and what goes wrong in diseases, such as cancer or neurodegenerative disorders. Signaling requires precise function of proteins, which often rely on phosphorylation/dephosphorylated cycle, a controlled process of addition and loss of a phosphate component. This cycle is orchestrated by enzymes called kinases that put on the phosphates and phosphatases that remove these modifications. “These are key enzymes that keep our tissues healthy,” said Jura. “Something happens to them – they change their protein structure due to a mutation, get abnormally activated or silenced, and then precise control of signaling pathways is gone. This then leads to disease because core functions of the cell, including decisions to survive, migrate, or die, are out of balance.”
Some signaling pathways inside the cell depend on PGAM5, a mitochondrial protein phosphatase whose genetic modification in mice results in mitochondria dysfunction and development of a neurodegenerative state reminiscent of Parkinson's Disease. Functions of PGAM5 include regulation of protein degradation, cell death, metabolism, and aging. However, mechanisms regulating PGAM5 activation and signaling are poorly understood. In fact, no one even understood what the PGAM5 protein looks like in an active state because its activity was linked to formation of large self-assembling complexes, according to Jura. It was also shown that PGAM5 can exist in two forms, soluble and bound to the mitochondrial membrane.
In recently published work, members of Jura’s lab used structural biology and high-resolution fluorescence imaging to overcome these difficulties and produce a molecular snapshot of PGAM5 – providing fascinating insights into how the protein functions. Their work led to the surprising discovery that soluble PGAM5 can adopt different states, including structures in which twelve PGAM5 molecules organized into rings and further stacked to form highly ordered filaments. These studies demonstrated that assembly into the ring is an essential determinant of efficient catalytic activation of PGAM5 and relies on molecular engagement of the unique pocket in the PGAM5 phosphatase.
Mitochondrial form and function are tightly linked and often controlled by assembly of large protein complexes. An exciting possibility is that PGAM5 oligomerization into rings and filaments could also occur on mitochondrial membrane, changing the way the mitochondria are internally organized. Now that they have the structure, Jura and colleagues will also be able to develop chemical compounds that influence PGAM5 assembly and function, by engaging the unique binding pocket in PGAM5. Such compounds might be of potential therapeutic interest in the treatment of neurodegenerative and metabolic diseases in which PGAM5 has been implicated.
The next step in the discovery process is to learn more about how the phosphatase and its different assemblies interacts with the mitochondrial membrane. Jura and her colleagues will use high-resolution microscopy to look into the cell and test their hypothesis that the structure of the PGAM5 protein helps determine the structure of the mitochondrion itself.
Collaborating for Advancement
The Jura Lab places a premium on collaboration, and this project could not be possible without close work with the Frost Lab, led by Adam Frost, MD, PhD. The project was spearheaded by a Tetrad graduate student, Karen Ruiz, who was instrumental in producing the PGAM5 protein and developing methods for its analysis, and Tarjani M. Thaker, a postdoctoral fellow with expertise in cryo-electron microscopy, who in collaboration with Lakshmi Miller-Vedam in the Frost lab determined the surprising organization of the phosphatase.
This project was funded by the Program for Breakthrough Biomedical Research (PBBR), which was developed to ensure that UCSF researchers are limited only by their imaginations. The program provides support for transformational ideas that defy conventional wisdom and would struggle to qualify for funding from more traditional grant makers, such as the National Institutes of Health (NIH).
“UCSF is driven by questions, not by the technical limitations of a lab. Collaboration is key and it’s a place where many people will come on board and get excited by an idea,” said Jura.