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Nanopore Technology Enables Single-Molecule Analysis of Protein Structures

A team of scientists, headed by the University of Oxford, has made a significant breakthrough in detecting modifications on protein structures. Their method, published in Nature Nanotechnology, uses cutting-edge nanopore technology to identify structural variations at the level of individual molecules, even within long protein chains. This advancement holds promise for better understanding protein functions and related biological processes.

Human cells are believed to contain around 20,000 genes responsible for encoding proteins. However, the actual number of proteins observed in cells is much higher, with over 1,000,000 different structures known. This discrepancy is due to post-translational modification (PTM), which happens after a protein is transcribed from DNA. PTM introduces structural changes, like adding chemical groups or carbohydrate chains to the individual amino acids that compose proteins. Consequently, a single protein chain can have hundreds of potential variations, leading to the vast diversity of proteins in cells. PTM plays a crucial role in expanding the functional capabilities of proteins and contributes to the complexity of biological processes within the human body.

These protein variants play crucial roles in biology as they enable precise regulation of complex biological processes within individual cells. Mapping and understanding this variation would provide valuable insights that could revolutionize our comprehension of cellular functions. However, producing comprehensive protein inventories has been a challenging and elusive goal until now. The recent breakthrough in detecting modifications on protein structures using innovative nanopore technology, as achieved by the team of scientists led by the University of Oxford, holds promise for advancing our understanding of these vital cellular mechanisms.

To address this challenge, researchers from the University of Oxford's Department of Chemistry have developed a method for protein analysis using nanopore DNA/RNA sequencing technology. In this technique, a controlled flow of water is used to capture and unfold 3D proteins, converting them into linear chains. These chains are then threaded through narrow pores, allowing only individual amino acid molecules to pass through. Structural variations in the proteins are identified by measuring changes in electrical current applied across the nanopore. Each molecule causes distinct disruptions in the current, providing a unique signature that allows for the identification of different protein variants. This innovative approach holds great promise for achieving comprehensive protein inventories and advancing our understanding of cellular functions.

The team's method proved highly effective in detecting three distinct post-translational modifications (PTMs) – phosphorylation, glutathionylation, and glycosylation – at the level of individual molecules, even for protein chains that were over 1,200 amino acids long. The method successfully identified modifications that were deep within the protein's sequence. Significantly, this approach does not necessitate the use of labels, enzymes, or additional reagents, making it a label-free and straightforward process. This achievement marks a significant step forward in protein analysis and provides a powerful tool for exploring the complexities of cellular functions without the need for complex chemical processes.

The research team suggests that the newly developed protein characterization method can be easily incorporated into existing portable nanopore sequencing devices. By doing so, researchers will be able to quickly construct protein inventories of individual cells and tissues. This advancement holds the potential to enable point-of-care diagnostics, allowing personalized detection of specific protein variants linked to various diseases, such as cancer and neurodegenerative disorders. This development could revolutionize the field of medical diagnostics and bring us closer to more targeted and effective treatments based on individual protein profiles.

Professor Yujia Qing, a contributing author from the Department of Chemistry at the University of Oxford, expressed that the newly developed method is both straightforward and potent, offering a wide range of possibilities. Initially, it enables the examination of individual proteins, especially those implicated in specific diseases. Looking ahead, the method has the potential to generate comprehensive inventories of protein variants within cells, leading to deeper insights into cellular processes and disease mechanisms. This breakthrough has the potential to revolutionize our understanding of biology and contribute to advancements in medical research and personalized medicine.

Professor Hagan Bayley, a contributing author from the Department of Chemistry at the University of Oxford and co-founder of Oxford Nanopore Technologies, emphasized the significant potential of the method. Being able to precisely locate and identify post-translational modifications and other protein variations at the level of individual molecules holds great promise for advancing our comprehension of cellular functions and molecular interactions. Furthermore, this breakthrough may pave the way for new opportunities in personalized medicine, diagnostics, and therapeutic interventions. The method's implications are far-reaching and have the potential to shape the future of medical research and healthcare.

Oxford Nanopore Technologies, which originated from Professor Bayley's research and was established as a spinout company in 2005, has emerged as a leader in next-generation sequencing technologies. The company's patented nanopore technology allows scientists to rapidly sequence nucleic acids (DNA and RNA) using portable and cost-effective devices, unlike traditional sequencing methods that often demand specialized laboratories. Oxford Nanopore devices have brought about a revolution in both fundamental and clinical genomics, with a significant impact during the COVID-19 pandemic. They played a crucial role in tracking the spread of new coronavirus variants, contributing to the understanding and management of the pandemic.

This work was carried out in collaboration with the research group of mechanobiologist Sergi Garcia-Maynes at King's College London and the Francis Crick Institute.


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