Sequencing Technology enables Protein Variant Detection


Research at the University of Oxford has led to a signifi cant breakthrough in detecting modifi cations on protein structures by employing nanopore technology to identify structural variations at the single-molecule level, even deep within long protein chains.


Human cells contain approximately 20,000 protein- encoding genes, which then also generate variants following a process known as post-translational modifi cation (PTM), which occurs after a protein has been transcribed from DNA.


Because PTM introduces structural changes, such as the addition of chemical groups or carbohydrate chains to the individual amino acids that make up proteins, there could be hundreds of possible variations for the same protein chain.


These variants play pivotal roles in biology, by enabling precise regulation of complex biological processes within individual cells and mapping this variation would uncover a wealth of valuable information that could revolutionise our understanding of cellular functions.


Now researchers at the University of Oxford’s Department of Chemistry have successfully developed a method for protein analysis based on nanopore DNA/RNA sequencing technology. In this approach, a directional flow of water captures and unfolds 3D proteins into linear chains that are fed through tiny pores, just wide enough for a single amino acid molecule to pass through. Structural variations are identified by measuring changes in an electrical current applied across the nanopore. Different molecules cause different disruptions in the current, giving them a unique signature.


The team successfully demonstrated the method’s effectiveness in detecting three different PTM modifi cations (phosphorylation, glutathionylation, and glycosylation) at the single-molecule level for protein chains over 1,200 residues long. These included modifi cations deep within the protein’s sequence. Importantly, the method does not require the use of labels, enzymes or additional reagents.


A chain of amino acids is captured, unfolded and translocated through an engineered protein nanopore. Changes in an electrical current applied across the nanopore detect post-translational modifi cations deep within the proteins (shown as circles, triangles, and hexagons). Image credit: Wei-Hsuan Lan and Yujia Qing


Yujia Qing


Initially, it allows for the examination of individual proteins, such as those involved in specifi c diseases. In the longer term, the method holds the potential to create extended inventories of protein variants within cells, unlocking deeper insights into cellular processes and disease mechanisms.’


The University’s Professor Hagan Bayley, also from the Department of Chemistry, a contributing author and co-founder of Oxford Nanopore Technologies, added: “The ability to pinpoint and identify post-translational modifi cations and other protein variations at the single- molecule level holds immense promise for advancing our understanding of cellular functions and molecular interactions. It may also open new avenues for personalised medicine, diagnostics and therapeutic interventions.”


Oxford Nanopore Technologies, a spinout company launched in 2005 based on Professor Bayley’s research, has become established as a front-runner in next-generation sequencing technologies. Oxford Nanopore’s patented nanopore technology enables scientists to sequence nucleic acids (DNA and RNA) quickly using portable, inexpensive devices – in contrast to standard sequencing, which typically requires dedicated laboratories.


Hagan Bayley


According to the research team, the new protein characterisation method could be readily integrated into existing portable nanopore sequencing devices to enable researchers to rapidly build protein inventories of single cells and tissues. This could facilitate point-of-care diagnostics, enabling the personalised detection of specifi c protein variants associated with diseases including cancer and neurodegenerative disorders.


Professor Yujia Qing, Department of Chemistry at Oxford, contributing author for the study said: ‘This simple yet powerful method opens up numerous possibilities.


Oxford Nanopore devices have revolutionised fundamental and clinical genomics and played a critical role during the COVID-19 pandemic in helping to track the spread of new coronavirus variants.


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.The research fi ndings were published in Nature Nanotechnology


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Pioneering frontiers: A year in review of ground-breaking life science research


valuable insights into potential interventions for melanoma, breast, and colorectal cancers.


Engineering edgeless human skin with enhanced biomechanical properties.


In a recent blog post, AMSBIO refl ects on the innovative life science and biomedical research conducted by its customers throughout 2023. From unravelling the complexities of cancer progression mechanisms to transforming wound care, AMSBIO proudly acknowledges its role in supporting these scientifi c endeavours.


One notable collaboration led by Dr Ashley M. Laughney from Weill Cornell Medicine and Dr Samuel F. Bakhoum from Memorial Sloan Kettering Cancer Center delved into the intricate mechanisms driving cancer metastasis. Their research unveiled the intricate interplay between chromosomal instability and the immune system, shedding light on the chronic activation of the cGAS–STING pathway and its contribution to creating a pro-metastatic tumour microenvironment. Using CAG-Luciferase lentiviral particles from AMSBIO in mouse models of breast cancer, the researchers monitored metastatic progression through bioluminescence. This ground-breaking research marks a signifi cant step toward advancing cancer therapies, offering


Professor Peter K. Sorger’s research group at Harvard Medical School showcased the effi cacy of spatial biology in identifying visual cancer biomarkers compared to traditional histology techniques. Utilising the ‘Orion’ platform, which enables the collection of H&E and high-plex immunofl uorescence images for cancer diagnosis, the study used FFPE tonsil and lung adenocarcinoma tissue from AMSBIO’s extensive biorepository. The research demonstrated that combining models of immune infi ltration and tumour-intrinsic features through multimodal tissue imaging signifi cantly improves the prediction of progression-free survival. This work underscores the platform’s potential for advancing clinical research and cancer diagnosis.


At Columbia University Irving Medical Center, Dr Hasan Erbil Abaci’s team employed Hyaluronan Binding Protein from AMSBIO in their ground-breaking study on engineered wearable edgeless skin constructs (WESCs). Traditional fl at skin constructs face challenges in covering intricate areas like hands after injuries. The WESCs, designed to replicate the enclosed 3D geometry of human skin, offer improved biomechanical properties and have the potential to revolutionise wound care for complex body sites, representing a signifi cant advancement in the fi eld.


Read the full blog ‘Exploring the Frontiers of Science: A Year in Review with AMSBIO’, that also includes reviews on research advances in 3D Neuromuscular Disease Modelling, Non-Coding RNA Peptides in Cancer Therapeutics, Breakthrough High-Throughput Single-Cell RNA Sequencing, and Evading Immune Rejection with Synthetic Immune Checkpoint Engagers.


More information online: ilmt.co/PL/7nwA 61705pr@reply-direct.com


Solutions in Science 2025


SinS brings together scientists and analytical chemists to discuss and explore the latest products, techniques, and analytical solutions.


Following the successes of the Solutions in Science (SinS) conference and exhibition in Cardiff in 2023, International Labmate, is pleased to announce that the next SinS event will be held on the 8th-10th July 2025. In partnership with the Royal Society of Chemistry (The RSC), BMSS, ChromSoc, and other like-minded associations, SinS will be the must attend networking and information gathering event for scientists and analytical chemists in 2025.


The fi rst SinS event held in Cardiff in 2023 was a monumental success, with exhibitors and attendees alike giving the event a remarkable rating of 100% excellent or good.


‘SinS’ brings together scientists and analytical chemists to discuss and explore the latest products, techniques, and analytical solutions. With sustainability in mind, one of the primary goals of SinS is to unite special interest groups into one large meeting, reducing travel and time commitments while enhancing networking and information-sharing capabilities.


SinS 2025 provides a unique platform for attendees to engage with cutting-edge solutions, foster collaborations, and stay at the forefront of analytical science. The conference and exhibition will be held from the 8th to the 10th of July 2025, for scientists across a diverse range of industries.


More information online: ilmt.co/PL/8xnp 61634pr@reply-direct.com


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