The Human Plasma Proteome

Abstract

The human plasma proteome holds the promise of a revolution in disease diagnosis and therapeutic monitoring provided that major challenges in proteomics and related disciplines can be addressed. Plasma is not only the primary clinical specimen but also represents the largest and deepest version of the human proteome present in any sample: in addition to the classical "plasma proteins," it contains all tissue proteins (as leakage markers) plus very numerous distinct immunoglobulin sequences, and it has an extraordinary dynamic range in that more than 10 orders of magnitude in concentration separate albumin and the rarest proteins now measured clinically. Although the restricted dynamic range of conventional proteomic technology (two-dimensional gels and mass spectrometry) has limited its contribution to the list of 289 proteins (tabulated here) that have been reported in plasma to date, very recent advances in multidimensional survey techniques promise at least double this number in the near future. Abundant scientific evidence, from proteomics and other disciplines, suggests that among these are proteins whose abundances and structures change in ways indicative of many, if not most, human diseases. Nevertheless, only a handful of proteins are currently used in routine clinical diagnosis, and the rate of introduction of new protein tests approved by the United States Food and Drug Administration (FDA) has paradoxically declined over the last decade to less than one new protein diagnostic marker per year. We speculate on the reasons behind this large discrepancy between the expectations arising from proteomics and the realities of clinical diagnostics and suggest approaches by which protein-disease associations may be more effectively translated into diagnostic tools in the future.

AFM fishing nanotechnology is the way to reverse the Avogadro number in proteomics

“…As a result, proteomics is limited by the concentration sensitivity of existing technologies that are unable, despite the successful development of MS, 2-D-electrophoresis, multidimensional chromatography, and a variety of other methods, to overcome the CSL of 10 212 M (Table 1) [6][7][8][9][10][11][12][13].…”

“…For the most part, the efforts of investigators engaged in proteomics are directed towards overcoming the dynamic concentration barrier, i.e., the problem of identification of low-abundant proteins (,10 210 M) against a background of high-abundant ones (.10 26 M) [10,14]. The dynamic range of protein concentrations in biomaterials is very broad and corresponds to values upwards of 10 12 .…”

Integration of carboxyl modified magnetic particles and aqueous two-phase extraction for selective separation of proteins

“…For the practical biological sample, protein-separation was difficult due to their concentration range and the tremendous heterogenity [1]. Magnetic particles have attracted more and more interest in protein separation not only due to their good biocompatible and superparamagnetic properties, but also their surface can be modified by a variety of active functional groups which play an important role in protein adsorption and affinity interactions.…”

Setup for human sera MALDI profiling: The case of rhEPO treatment

“…Despite the strong potential of MALDI, the main issue to face remains the serum dynamic range (i.e. the range of serum protein concentrations from high-to low-abundance proteins, estimated in ten orders of magnitude [11]) which encompasses eight orders of magnitude the capacity of the mass spectrometer to discriminate species in complex mixtures [12][13][14][15] preventing the detection of biomarkers from picogram to femtogram levels, such as prostate specific antigen (PSA) or interleukins, leaving undisclosed a large number of proteins and peptides. So far, to overcome this issue, an adequate fractionation step prior proteomic analysis is mandatory in order to remove high-abundant components.…”