Structural protein variants detected through nanopore technology

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Scientists claim to have achieved a breakthrough in detecting modifications in protein structures by using nanopore technology to identify structural variations at the single-molecule level, even deep within long protein chains.

The method was described in Nature Technology by a team from the University of Oxford who say that initially, the technology should enable the examination of individual proteins, such as those involved in specific 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,” Yujia Qing, a chemistry professor at Oxford University and a contributing author of the study, said.

Human cells contain approximately 20,000 protein-encoding genes. However, the actual number of proteins observed in cells is far greater, with over 1 million different structures known.

These variants are generated through a process known as post-translational modification (PTM), which occurs after a cellular protein has been transcribed from DNA. PTM introduces structural changes that result in hundreds of possible variations for the same protein chain. The researchers say that mapping these variations could “revolutionize” the understanding of cellular functions.

The Oxford team developed a method for protein analysis based on nanopore-based sensing technology. A directional flow of water captures and unfolds 3D proteins into linear chains that are then fed through tiny pores. 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 modifications (phosphorylation, glutathionylation, and glycosylation) at the single-molecule level for protein chains over 1,200 residues long, including discerning modifications deep within the protein’s sequence. Importantly, the method does not require the use of labels, enzymes, or additional reagents.

According to the team, the new protein characterization method could be readily integrated into existing portable nanopore sequencing devices to help rapidly build protein inventories of single cells and tissues. They added that this capability could facilitate point-of-care diagnostics, enabling the personalized detection of specific protein variants associated with diseases such as cancer and neurodegenerative disorders.

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