What Is Proteomics

First introduced in 1995 (1), the term proteome refers to the entire group of proteins associated with a given genome. All cells of a given organism contain an equivalent genomic content. The proteome, however, does not represent all possible proteins that the genome can express. Selective gene expression during development and differentiation, and in response to external stimuli, results in each cell expressing only the fraction of encoded proteins relevant to its functional state at any given time. Thus, one can speak not only ofthe general human proteome but also more specifically ofthe proteome ofpar-ticular cells such as cardiomyoctes, tissues such as the heart, and even of subproteomes that correspond to particular organelles or biological compartments such as the inner mitochondrial membrane.

Conversely, the proteome extends beyond the expression profile of a particular genome. A number of studies suggest that gene expression often correlates poorly with protein levels (2,3). Although protein expression is influenced by the rate of transcription, nucleotide and protein half-lives vary, such that the presence or absence of mRNA may not accurately reflect the presence or absence of the corresponding protein. Additional co- or posttranslational events may affect protein stability. Thus, mRNA sometimes reveals surprisingly little about protein abundance and is also an imperfect predictor of posttrans-lational regulation.

The proteome associated with a particular gene set includes all variants of the same protein that result as a consequence of differential cellular processing (see Fig. 1). Transcription initiation sites may vary for the same protein. Subsequently, as many as one-fourth or more of higher eukaryotic genes can be alternatively spliced, resulting in multiple transcripts. Following transcription, the protein may undergo (often on multiple sites) one or more of greater than 200 potential posttranslational modifications (such as phosphorylation, glycosylation, acetylation, and sulfation). Subsequent additional enzymatic and nonenzymatic alterations culminate in a greatly expanded number of simultaneously existing molecular species. The one gene-one protein dictum, now no longer tenable, had led few to anticipate the immense magnitude and complexity ofthe resulting proteome.

Fig. 1. Relationship between the genome and proteome.

Proteomics uniquely offers insight into disease because proteins and their bioenzyma-tic functions largely determine the phenotypic diversity that arises from a set of common genes. Posttranslational modifications help regulate structure, function, localization, maturation, and turnover of proteins. Because the entire complement of expressed proteins in their various forms can rapidly change in response to environmental cues, the proteome represents the unique ensemble ofproteins that reflects the state ofthe cell or group of cells at a given time in a particular context under particular stimuli. Thus, the proteome is highly dynamic, in contrast to the stability of the genome. This complexity is the basis ofboth its great informative potential and analytic challenge. Because most pathologies result from protein alterations as either cause or effect, whether by genetic disposition or environmental/pharmacological factors, proteins serve as natural biomarkers and potential therapeutic targets.

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