Proteins are the tireless workhorses within our cells, orchestrating a symphony of intricate tasks. Much like a toolkit filled with mechanical implements, each protein adopts a three-dimensional shape selected for a specific purpose. Just as a screwdriver navigates the twists of screws, cellular proteins waltz through their designated roles. However, consider the screwdriver suddenly bending out of shape. The result: a loss of function and a disruption of the task at hand. This mirrors the fate of certain proteins; when they adopt abnormal shapes, they can become the drivers behind devastating neurodegenerative diseases such as Alzheimer's, Parkinson’s or ALS that emerge during aging.
Within this enigma lies the promise of understanding. By mapping out the diversity of protein structural states, it is possible to illuminate the intricate machinery of cellular function. In a pioneering study published in Molecular Cell, the team embarked on this mission by mapping structural alterations in cellular proteins during the aging process and, in the process, identifying new ways aging impacts how cells hum with life
"Aging is a complex biological process characterized by the gradual loss of cellular functions. Our goal was to take a fresh and unbiased look at this process by mapping how the function of different cellular proteins might be affected by aging. By comparing the structural features of thousands of proteins between young and aged yeast cells and positioning these changes to known and predicted protein structures, we constructed a comprehensive map of how individual proteins and corresponding cellular processes are affected by aging. This resulted in an information-rich catalog, which we used to assess the consequences of these changes on the function of aging cells," says Juha Saarikangas, the study's lead author.
Preventing proteins from sticking together enabled cells to live longer
One of several findings resulting from this approach was the discovery of a metabolic enzyme responsible for synthesizing the amino acid glutamate. During aging, this structurally symmetric enzyme starts adhering to one another, forming linear polymers resembling a pile of Lego bricks.
"We observed that subtle changes occurring in the cellular environment during aging promote the formation of these protein polymers," says Jurgita Paukštytė, PhD student and first author of the publication.
To understand the role of these polymers, the authors leveraged information from their structural proteomics to identify the interfaces that mediated the self-assembly of this enzyme. They introduced mutations that reduced the stickiness of these interfaces, thereby preventing the formation of polymers.
"Our experiments revealed that when this enzyme forms polymeric assemblies, it acquires a new function that leads to the accumulation of amino acids within the aging cells. This accumulation creates issues for the mitochondria. Remarkably, by preventing proteins from sticking together, we could mitigate these problems, resulting in cells that live longer," explains Paukštytė.
Since many age-associated diseases are driven by proteins that abnormally adhere to each other, this study holds the promise of providing better detection and intervention strategies for diseases caused by abnormal protein structures. "The strength of our approach lies in detecting these changes with sufficient resolution in protein structure that enabled us to experimentally prevent proteins from sticking together, thereby alleviating the issues they cause during aging," she continues.
Overall, this study sheds light on the intimate relationship between protein structure and function, opening new avenues for the scientific community to explore.
”We identified structural alterations in hundreds of proteins during aging, but have, so far, only had the resources to work with a handful of them. Therefore, there is still much to discover regarding what these changes can tell us about the aging process. Furthermore, a key insight stemming from our study was the connection between protein polymerization and aging. Many enzymes can form similar polymers, and I anticipate that we will identify more instances of these being influenced by aging, making them candidates to drive some of the metabolic alterations in aging cells," concludes Saarikangas.