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Abstract
Proteins have several measurable features in biological fluids that may change under pathological conditions. The current disease biomarker discovery is mostly based on protein concentration in the sample as the measurable feature. Changes in protein structures, such as post-translational modifications and in protein–partner interactions are known to accompany pathological processes. Changes in glycosylation profiles are well-established for many plasma proteins in various types of cancer and other diseases. The solvent interaction analysis method is based on protein partitioning in aqueous two-phase systems and is highly sensitive to changes in protein structure and protein–protein- and protein–partner interactions while independent of the protein concentration in the biological sample. It provides quantitative index: partition coefficient representing changes in protein structure and interactions with partners. The fundamentals of the method are presented with multiple examples of applications of the method to discover and monitor structural protein biomarkers as disease-specific diagnostic indicators.
Clinical diagnostic protein biomarkers are currently defined as proteins in biological fluids (i.e., plasma, serum, CSF, urine) whose concentrations change under pathological conditions. Recent publications indicate significant variability for multiple proteins in biological samples, indicating that the concentration of a specific protein may not be reliable disease-specific indicator.
Structural properties and protein–partner interactions existing in biological fluids are pathology-specific.
Structural protein biomarker may be defined as a protein undergoing changes in structure or interactions with binding partners as a result of pathology.
Post-translational protein modifications, such as glycosylation, occur in concert with emergence of many pathological processes, such as in cancer.
Solvent Interaction Analysis (SIA) is based on analytical application of protein partitioning in aqueous two-phase systems. SIA is inexpensive, simple, and clinical lab-friendly method for discovering and monitoring changes in the protein structure and protein–protein interactions directly in biological fluid.
The SIA method was demonstrated to be capable of quantitative analysis of different types of protein–water (dipole–dipole, hydrogen bonding and electrostatic) interactions.
SIA could detect changes in the protein structure, folding, and conformation, aggregation propensity, protein–protein and protein–small molecule interactions for isolated proteins and in biological fluids.
SIA has been demonstrated to be applicable for discovery and monitoring of structural protein biomarkers in prostate, breast and ovarian cancers.
SIA method is a ratiometric technique providing a quantitative structural index that is independent of the protein concentration in the biological fluid. It could also be used to define an overall structural index in heterogeneous diseases such as cancer.
Acknowledgements
The authors gratefully acknowledge stimulating discussion and help of A Zaslavsky (University of Michigan, Ann Arbor, MI, USA) in writing this paper.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.