Short-lived proteins

Cytokines are small, short-lived proteins and important mediators of local intercellular communication. They play a key role in integrating responses to a variety of stimuli in immune and inflammatory processes. By binding their cognate receptors on target cells in their immediate vicinity, these molecules participate in many important biological activities including cell proliferation, activation, death and differentiation. In... 

The dosing regimens can be quite variable and at times very techniqueintensive. These chemicals are almost always administered by a parenteral route of administration normally intravenously or subcutaneously. Dosing regimens have run the range from once every two weeks for an antihormone vaccine to continuous infusion for a short-lived protein. 

Gonda, D. K. and Varshavsky, A. A multi ubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science, 1989, 243, 1576-1583. 

Rate of turnover In healthy adults, the total amount of protein in the body remains constant, because the rate of protein synthesis is just sufficient to replace the protein that is degraded. This process, called protein turnover, leads to the hydrolysis and resynthesis of 300 to 400 g of body protein each day. The rate of protein turnover varies widely for individual proteins. Short-lived proteins (for example, many regulatory proteins and misfolded proteins) are rapidly degraded, having half-lives measured in rrh-utes or hours. Long-lived proteins, with half-lives of days to weeks, constitute the majority of proteins in the cell. Structural proteins, such as collagen, are metabolically stable, and hare half-lives measured in months or years. 

Many short-lived proteins are degraded within the cytosol in ATP-dependent processes. A major process involves the small protein ubiquitin (Box 10-C).134 Once "labeled" by formation of an isopeptide linkage to ubiquitin, a peptide is attacked by proteases in the proteasome complexes (Box 7-A, Chapter 12). There it is quickly degraded. Other proteases, most of which do not require ATP, are also present in the cytoplasm (Chapter 12). How do these enzymes as well as those within the lysosomes work together to produce a harmonious turnover of the very substance of our tissues How is it possible that one protein has a long half life of many days while another lasts only an hour or two in the same cell The answer seems to be that... 

Bachmjuir, A., and A. Varshavsky, The degradation signal is a short-lived protein. Cell 56 1019-1032, 1989. 

The mechanisms whereby GH and other factors modulate receptor levels is not known. In medium- or long-term experiments use of protein synthesis inhibitors usually blocks such modulation, suggesting that de novo synthesis of receptors may be required, although involvement of other short-lived proteins cannot be ruled out. Rapid increase in receptor levels probably does not require synthesis of new receptors, and may be achieved by insertion of receptors that were previously stored in-tracellulqrly into the plasma membrane, and/or by activation of receptor proteins already in the plasma membrane in an inactive form. Down-regulation of receptors probably involves endocytosis, possibly followed by degradation [18]. 

The ubiquitin-proteasome pathway is a central route for the selective degradation of intracellular short-lived proteins proteolysis, an essential metabolic process... 

Heinemann, E. S., and Ozols, J. Stearoyl-CoA desaturase, a short-lived protein of endoplasmic reticulum with multiple control mechanisms. Prostaglandins Leukot Essent Eatty Acids 68 (2003) 123-133. 

Enzymes catalyzing rate-determining steps in metabolic pathways are also short-lived. Protein breakdown may thus be an important regulatory mechanism for a protein. 

PEST sequences - Virtually all short-lived proteins (i.e., half-lives less than 2 hours) contain one or more regions rich in proline, glutamate, serine, and threonine. These regions are called PEST sequences because the one-letter codes for these amino acids are P,E,S, and T, respectively. Very few longer-lived proteins contain these sequences. Furthermore, insertion of these sequences into long-lived proteins increases their metabolic lability. 

Short-lived proteins and energy-dependent degradation... 

Much effort has been spent trying unravel the mechanism by which short-lived proteins are selected for degradation by an ATP-dependent mechanism. 

LBG did not influence carbohydrate metabolism sufficiently to alter glycosylated hemoglobin levels despite lowering blood lipids.34 More sensitive techniques of protein glycosylation have recently become available and glycosylation of short-lived proteins might be useful in retrospective evaluation of possible recent hypoglycemic episodes. 

Pan, J.X., Han, J., Borchers, C.H., Konermann, L. (2010) Characterizing short-lived protein folding intermediates by top-down hydrogen exchange mass spectrometry. Analytical Chemistry, 82 (20), 8591-8597. 

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