Exploring the Role of Protein Barcodes and Next-Generation Protein Sequencing™ for ProteinConformation High-Throughput Mapping
Sponsored Content by Quantum-SIMay 29 2024Reviewed by Aimee Molineux Proteins can adopt a range of specific conformations, some of which significantly contribute to the pathology of many diseases.
The focus of the research Dr. Serebryany’s team’s main area of interest is the biophysics of protein misfolding in vivo and the mechanisms of misfolding-associated diseases. They are also concerned with the discovery and pharmacological targeting of physiologically relevant non-native protein conformations and protein engineering in environments currently deemed inaccessible.
Proteins can assume the correct, fully folded state through this catalytic process. The same enzyme also collects misfolded proteins found in the ER. Disulfide scanning mutagenesis is a well-defined approach for determining how particular double-cysteine variants of a protein form intramolecular disulfide bonds.
This makes it possible to unpack the 3D structural space of a protein into subgroups consisting of one-dimensional sequence space via disulfide cross-links. From there, the sequence can be mapped to establish whether a given pair of cysteine residues can covalently bind to one another. Having already published this method in Molecular Cell in 2023 and as a proof of concept, Dr. Serebryany and his team applied the technique to HdeA, an inherently disordered protein chaperone found in E.
We can also assess the changes in the protein molecule's biophysical properties in vivo that emerge from forming individual disulfides that trap certain conformations. While this method has demonstrated successful outcomes to a certain extent, it still has limitations. The cysteine residues must remain close together in the sequence because mass spectrometry cannot cope with extremely long peptides. Moreover, any intervening cysteines must be eliminated between the two introduced cysteines. Otherwise, a cut between the two introduced cysteines can occur, resulting in a complete loss of all the structural information.
Therefore, the barcode sequences should be around four, five, or six residues. This would also depend on the complexity of the library required. Barcodes that share the same amino acid composition can be challenging to sequence using mass spectrometry because they would yield the same single precursor ion.
HTDS and Next-Generation Protein Sequencing With new methodologies supported by innovative technologies, the potential becomes rather expansive. This, in turn, would enable several different types of biophysical measurements, including thermodynamic stability, binding affinity to a target, or aggregation propensity, at much greater throughputs than traditional methods.
Next-Generation Protein Sequencing™
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