Cancer protein p53 observed in action reveals more order than expected
Cancer occurs when cells divide uncontrollably and displace healthy cells. Tumor suppressors provide an important defense against this. As molecular growth inhibitors, they prevent healthy cells from becoming cancerous. A key protein among them is p53, also known as the "guardian of the genome." If p53 detects errors in a cell's DNA, it stops the cell from dividing. If the DNA is irreparably damaged, p53 triggers cell death. To perform these tasks, the protein interacts with many other proteins. However, if p53 is inhibited or altered, cells continue to divide despite damage—and a tumor develops. More than half of all tumors are associated with p53 failing to fulfill its function properly within cells.
Order versus disorder: Two classes of proteins
Like all proteins, p53 is built from a long chain of amino acids. While around 70% of human proteins fold into a well-ordered three-dimensional structure that enables them to perform their cellular function, p53 belongs to the remaining 30% that lack any fixed structure. These proteins are flexible, partially form tangled chains and constantly change their three-dimensional shape. They are therefore termed intrinsically disordered proteins (IDPs).
Protein dynamics across many time scales, spanning seven orders of magnitude
Proteins are very small and move extremely fast. The same applies to p53. Some structural changes of p53, however, take longer to complete, while others take less time. To fully understand all the internal movements of the cancer protein in action, its dynamics must therefore be tracked across a broad range of very different time scales.
Researchers led by Helmut Grubmüller and Christian Griesinger at the Max Planck Institute for Multidisciplinary Sciences (MPI-NAT) in Göttingen, Germany, have now visualized, for the first time, how the p53 protein changes dynamically across time scales spanning seven orders of magnitude—from picoseconds (one trillionth of a second) to microseconds (one millionth of a second), which elapse comparatively slowly. They discovered structural dynamics that were far more diverse and complex than previously thought: Depending on the time scale at which p53 was observed, the protein showed very different dynamics.
"One second in a human's life corresponds to one trillionth of a second for a protein. To put it in everyday terms, imagine a pedestrian zone," explains Grubmüller, head of the Department of Theoretical and Computational Biophysics at MPI-NAT. "In real time, you see people walking through the streets. If you film at a time-lapse speed 1,000 times faster, people appear to move so fast that they blur, and processes 1,000 times slower become visible, such as a construction site emerging and disappearing or a festival unfolding.
"An even more extreme time-lapse at a further 1,000 times compression reveals even slower processes, such as entire houses being built. The situation is similar with p53. Following this analogy: Until now, we only knew about the pedestrians—construction sites, festivals and house construction were invisible to us."
Observation gap closed
So far, no method was available to observe a protein in action simultaneously in slow motion and time-lapse for such long periods. In a 10-year research project, teams led by Griesinger and Grubmüller have now developed a method to make this possible. They used molecular dynamics simulations on high-performance computers to track p53 structures; these predictions were then confirmed experimentally using high-resolution nuclear magnetic resonance (NMR) spectroscopy.
"One of the key factors in our success was having access to an NMR spectrometer at the institute with a 1.2 gigahertz frequency, which is one of the 15 most powerful in the world," said Supriya Pratihar, one of the two joint first authors of the paper published in the journal Nature Communications. Only this NMR spectrometer, which pushes current technological limits, provided sufficient resolution and sensitivity to detect even transient structures that are essential for p53's function.
More stable structures than expected
"p53 surprised us by forming stable three-dimensional structures even without a binding partner protein. These take a very long time to form and are extremely short-lived. This is why they had been overlooked in experiments until now," says Dániel Szöllösi, also a first author of the study.
The researchers identified more than 50 different three-dimensional structures. "In order to perform its functions within the cell, p53 must interact with a wide variety of proteins. The variety of its structures could be crucial to its ability to bind such a large number of proteins," says Griesinger, head of the Department of NMR-Based Structural Biology at the institute. "In the fight against cancer, understanding the dynamics of these structures might help develop drugs that target p53."
A tool for studying other IDPs
These findings could also contribute to research on other diseases: IDPs play a major role in neurodegenerative diseases such as Alzheimer's and Parkinson's. Through their work, the researchers are providing a valuable tool for investigating such disordered proteins and revealing their previously unknown structural dynamics.
This article was originally published on MedicalXpress Breaking News-and-Events.