Protein Turnover: A Functional Appraisal

Abstract

Pioneering works of Schoenheimer and his colleagues (Schoenheimer, 1942) were the first to recognize 'the dynamic state of body constituents'. Prior to that time, the cell was viewed as a chemical engine, burning exogenous fuels, but which did not itself undergo metabolic transformations. Now, however, comprehensive evidence indicates that cellular proteins are in a continual state of renewal, and that the general properties of protein turnover are similar in prokaryotes and in eukaryotes. Essentially all proteins in living organisms undergo continual replacement, although there is marked heterogeneity between fractional rates of replacement of different proteins, as well as between the same proteins in different tissues, and the great majority of protein turnover is intracellular (e.g. Goldberg & Dice, 1974; Schimke, 1975; Goldberg & St. John, 1976; Ballard, 1977; Millward, Bates & Rosochaki, 1981; Fauconneau, 1985; Mayer, 1987; Houlihan et al., 1988; Bradshaw, 1989). There are several pathways of protein degradation within cells (Dice, 1987; Bradshaw, 1989). Different rates of renewal under normal metabolic conditions are effected by selective degradation that is mostly non-lysosomal, involving calciumdependent proteolysis, as well as the ubiquitindependent pathway in which each protein is first 'targeted' by conjugation with ubiquitin molecules (Hershko et al., 1980; Ciechanover, Finley & Varshavsky, 1984; Wheatley, 1984; Ciechanover, 1987; Varshavsky, Bachmair & Finley, 1987; Gonda et al., 1989; Bachmair & Varshavsky, 1989). Alternatively, pathways by which proteins are taken up and digested in lysosomes are non-selective and inducible, being active primarily under circumstances of nutrient deprivation or stress (Dice & Chiang, 1989). In the present contribution, protein turnover refers specifically to the continuous degradation and renewal of intracellular proteins that are hydrolysed to their component amino acids, and replaced by an equal amount of freshly synthesized protein. Protein metabolism is comprised of the two separate processes both of protein degradation and protein synthesis, which may vary in the same or in opposite directions (e.g. Rennie et al., 1983; Muramatsu et al., 1987). Each process must therefore be measured to quantify turnover and identify alterations effecting changes in net balance. Under conditions of growth, rates of protein turnover are equivalent to associated rates of protein degradation. Such renewal may occur at surprising intensities. Although relatively insignificant in procaryotes, a minimum of 77% of whole-body protein synthesis effects turnover rather than net deposition among mammals generally (e.g. Waterlow, Garlick & Millward, 1978; Reeds et al., 1980). Alternatively, during periods of net protein loss and wasting, protein turnover equates with rates of protein synthesis. A variety of techniques for the measurement of these processes includes both precursor methods and end-product methods, each with potential pitfalls, but which may provide reasonable accuracy as discussed comprehensively elsewhere (e.g. Waterlow et al., 1978; Reeds & Lobley, 1980; Garlick & Fern, 1985; McNurlan & Garlick, 1989). Given associated energy costs, why should protein turnover be necessary at all? Schoenheimer (1942) believed that protein breakdown was of equal significance to protein synthesis in providing the flux that renders biological systems so dynamic and adaptable. Since then, molecular and biochemical research have continued to reveal important regulatory functions of proteins. Indeed, amino acids are now known to be the precursors of modulating molecules which include nucleic acids, haem, neurotransmitters, hormones, proteases, opioid peptides (Giugliano et al., 1988) and chaperones (Sambrook & Gething, 1989). Realization of the generality of protein turnover, and that breakdown is as important as