Protein Turnover

Protein turnover occurs because of the presence within cells of proteolytic systems that degrade


Genetic determinants

Skeletal muscle

Visceral organs f ;-t

Physical activity y


Free amino acid pool

Dietary protein

Insulin, IGF1,

T3 etc.

Figure 1 Protein-stat mechanism for coordinated control of body protein growth and maintenance. The protein content of skeletal muscle is controlled by long bone growth mediated through a passive stretch mechanism and anabolic signals in response to dietary protein intake, with the growth of most other organs secondary to this interaction—that is, growth rate for these organs is a function of metabolic and functional demand in response to food intake.

proteins for a variety of reasons ranging from the removal of proteins with an incorrect primary amino acid sequence ("error" proteins) to the provision of free amino acids during nutrient deprivation. However, the half-lives of individual proteins vary over at least three orders of magnitude within the same cells, identifying the process as specific. The nature and control of proteolysis are poorly understood. The physicochemical structure, especially hydrophobicity and ionic charge, influences susceptibility to proteolysis. Also, an amino acid sequence (PEST: proline, glutamate, serine, and threonine) influences susceptibility to proteolysis and occurs in several rapidly degraded proteins. The molecular basis for this remains largely unknown. For heterogeneous turnover of proteins within structures such as mitochondria, myofilaments, and multienzyme complexes to occur while functional integrity is maintained, complex coregulation is required, and there is evidence for at least three different systems involved in the case of skeletal muscle.

The lysosomal-autophagic system is present in all cells and involves acid proteinases (cathepsins) within a distinct vacuolar structure capable of engulfing and degrading complete organelles, ribosomes, as well as individual intracellular proteins and proteins entering cells via endocytosis. Lysosomal proteolysis is complete, and most is known about hepatic macroautophagy in which hepatic protein mass appears to be regulated by a receptor-mediated amino acid-dependent inhibitory process.

The ubiquitin-proteasome system is widely distributed among tissues, with a relatively broad protein specificity, catalyzing the hydrolysis of protein to peptides averaging approximately 8

amino acids long and exhibiting an ATP dependency. It involves two components. One is a recognition system involving ATP-dependent formation of a covalent link between the protein and a short polymer of ubiquitin, which is responsible for targeting the protein substrates toward pro-teolysis. This phase involves three separate reactions: ATP-dependent activation of ubiquitin, conjugation of ubiquitin to cellular proteins, and proofreading of the conjugates to either regenerate the target protein by removal of ubiquitin or commit the target protein to proteolysis by further ubiquitinylation. Proteolysis is mediated by the giant multifunctional protease, the protea-some. This comprises a core particle made of duplicate sets of at least 14 different proteins assembled in groups to form rings that are in turn stacked to form a donut-like structure within which the ubiquitin-conjugated proteins are unfolded by another ATP-dependent process and proteolytically cleaved to form peptides. A regulatory particle both delivers the ubiquitin-conju-gated proteins to the core particle and removes ubiquitin from the peptides released after proteo-lysis. Proteolysis of the peptides is achieved by other systems, including the lysosomal system since degradation of ubiquitinylated proteins can also be achieved by the lysosome, or other poorly described proteinases and peptidases including the giant protease tripeptidyl peptidase II (TPP II) and various aminopeptidases. The relative importance of the two main systems capable of complete proteolysis, the lysosome and the proteosome, in various tissues remains uncertain. Most work on the regulation and activation of the ubiquitin-proteasome system has involved the accelerated proteolysis in skeletal muscle atrophy, antigen processing, and removal of aberrant proteins rather than basal and nutritionally sensitive proteolysis. The third proteolystic system involves calpain and calpastatin, a calcium-activated proteolytic pathway that can initiate but not complete proteolysis. This comprises a highly conserved family of non-lysosomal calcium-dependent cysteine proteases composed of two ubiquitous isoforms (calpain I and II), several tissue-specific isoforms, and a 28-kDa regulatory subunit (calpain 4). In vivo calpain activity is tightly regulated by its endogenous and highly specific inhibitor, calpastatin. There is little evidence to suggest a role in nutritionally sensitive basal proteolysis.

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