Long-lived proteins

This paper will focus on methods that are based on the analysis of long-lived protein adducts of CW agents which are detectable weeks or even months after exposure. Examples of real exposure incidents will be described. 

DE seems to be the best analysis technique for highly expressed, abundant, long-lived proteins. However, most of the biologically significant proteins are expressed at low levels and are rapidly turned over. Thus, other analytical approaches are often preferred for the analysis of such proteins. 

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. 

Eukaryotic cells degrade proteins within both the cytosol and lysosomes. Lysosomes apparently take up many proteins but have a preference for N-terminal KFERQ132 and also for particular types of glycosylation (Chapter 20). Lysosomes act on many long-lived proteins.1331333 Once within the lysosomes, the proteins are broken down into amino acids with a half-life of 8 minutes. During nutritional deprivation, the rate of uptake of proteins by lysosomes increases markedly. The same is true during certain developmental changes, for example, when a tadpole loses its tail. 

The modification by AGE of even less long-lived proteins is also possible. Makita et al.m were able to show by means of AGE-specific antibodies that circulating... 

Proteins with relatively short half-lives are glycated by rather acute increases in blood glucose, whereas chronic, small elevations of blood glucose lead to irreversible chemical modifications of long-lived proteins. These have been called advanced-glycation end-products (AGEs) (Fig. 8.2). 

Double-labeled proteins from rat liver cytosol ( C in long-lived, in short-liv J proteins after in vivo labeling) have been used as substrates for proteinases in vitro. The differences in the degradation rates of short-lived and long-lived proteins in vitro by different proteinases in the presence or absence of different effectors enabled conclusions to be drawn concerning their role in in vivo turnover. The main activity of lysosomal proteinases at pH values of 6.1 and 6.9 was found to be caused by thiol proteinases which decompose short-liv l cytosol proteins preferentially. Autolysis of double-labeled cell fractions showed a remarkably faster breakdown of short-lived substrate proteins only in the soluble part of lysosomes >. 

Little attention has been devoted to the relation of late browning reactions to human metabolism. However, in considering long-lived proteins in man (e.g., lens crystallins, collagens, glomerular basement membrane), it is apparent that such reactions may be relevant to aging processes. 

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. 

Autophagy is a cell survival mechanism that involves degradation and recycling of cytoplasmic long-lived proteins and organelles. In addition, autophagy mediates... 

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