Molecular Mystery Solved – Harvard Scientists Discover a Previously Unknown Way Cells Break Down Proteins

Harvard Researchers Uncover New Process of Cellular Protein Breakdown

A recent breakthrough by scientists at Harvard University has shed light on a previously unknown mechanism through which cells break down proteins, revealing implications for various biological functions and potential therapeutic applications. This discovery has the potential to address conditions arising from protein imbalances within cells.

The identified mechanism primarily targets short-lived proteins that play pivotal roles in neural, immune, and developmental genes. These proteins, originating within the cell nucleus, are swiftly degraded once their function is fulfilled, influencing critical processes such as brain connectivity and immune responses.

The degradation process had remained an enigma for decades, confounding researchers. However, through a collaborative effort spanning different departments at Harvard Medical School, a protein known as midnolin was pinpointed as a key player in the degradation of numerous short-lived nuclear proteins. The study’s findings propose that midnolin directly seizes these proteins, guiding them into the cellular waste-disposal system known as the proteasome, where they undergo destruction.

The study’s co-lead author, Xin Gu, who is a research fellow in neurobiology at HMS, noted that although these short-lived proteins have been recognized for over four decades, their degradation process remained elusive. The team’s discovery presents a clear and elegant mechanism that might hold considerable implications for future applications.

Traditionally, cells have been understood to break down proteins using a molecular “tag” called ubiquitin, which signals the proteasome to dispose of unneeded proteins. Yet, the proteasome’s ability to degrade proteins without ubiquitin tags raised suspicions about an alternative, ubiquitin-independent degradation mechanism.

The research team focused on a group of proteins known as stimuli-induced transcription factors, which are swiftly produced in response to cellular cues and then rapidly destroyed after their gene activation task is completed. This group of proteins plays a vital role in diverse biological processes.

The identification of midnolin as a protein involved in breaking down these transcription factors marked a significant step forward. The researchers utilized sophisticated genetic and protein analysis techniques, further supported by a machine learning tool named AlphaFold, to unravel the details of midnolin’s mechanism. They uncovered a “Catch domain” within midnolin that captures various proteins and funnels them into the proteasome, ultimately leading to their degradation.

The implications of this discovery extend to potential therapeutic applications. By targeting this mechanism, scientists could potentially control protein levels and manipulate associated biological functions, thereby rectifying dysfunctions. The researchers are particularly interested in exploring how this mechanism could be fine-tuned to specifically degrade proteins of interest, holding promise for disorders and diseases rooted in protein deregulation.

This groundbreaking study not only elucidates a previously mysterious cellular process but also unveils a pathway with potential implications for medical advancements. The researchers’ future plans involve deeper structural studies and investigations into midnolin’s role in different cellular contexts and developmental stages. The potential to harness this mechanism to address a range of disorders underscores the significance of this discovery in the realm of biological research and therapeutic development.

Reference: Gu, X., Nardone, C., Kamitaki, N., Mao, A., Elledge, S. J., & Greenberg, M. E. (2023). The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation. Science, 25 August 2023. DOI: 10.1126/science.adh5021

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• Harvard Medical School
• AlphaFold
• Science Journal
• Damon Runyon Cancer Research Foundation
• National Science Foundation
• National Institutes of Health