Introduction

How does the cell know which proteins to degrade, and when?

Protein molecules are continuously synthesised and degraded in all living organisms. The concentration of individual cellular proteins is determined by a balence between the rates of synthesis and degradation, which in turn are controlled by a series of regulated biochemical mechanisms. Differences in the rates of protein synthesis and breakdown result in cellular and tissue atrophy (loss of proteins from cells) and hypertrophy (increase in protein content of cells).

The degradation rates of proteins are important in determining their cellular concentrations. Protein degradation exhibits first-order kinetics unlike protein synthesis, which is zero-order. Protein degradation is energy dependent, requiring ATP, and is limited by the concentration of the reactants, whereas protein synthesis cannot be completed in the absence of any one of the necessary reactants.

Proteins breakdown at rates, ranging from 100% per hour to less than 10% per hour and their half-lives (time taken for loss of half the protein molecules) vary between 24h and 72h. Regulatory enzymes and proteins have much shorter half-lives of the order of 5-120min. Protein breakdown can take place in the mitochondria, chloroplasts, the lumen of the endoplasmic reticulum and the endosomes, but occurs most commonly in one of two major sites of intracellular proteolysis, lysosomes and the cytosol. The individual degradation rates of proteins vary within a single organelle or cell compartment and also from compartment to compartment, due either to differing sensitivity to local proteases or differing rates of transfer to the cytosol or lysosomes. The range of protein degradation rates within a single organelle is limited, suggesting that the proteins may be treated as groups or families.

Most non-selective protein degradation takes place in the lysosomes, where changes in the supply of nutrients and growth factors can influence the rates of protein breakdown. Proteins enter lysosomes by macroautophagy, that is the enclosure of a volume of the cytoplasm by an intracellular membrane. The rates of lysosomal degradation can vary greatly with cell type and conditions, ranging from less than 1% of total cell protein per hour to 5-10% per hour. The lysosomal degradation of some cytosolic proteins increases in cells deprived of nutrients. It is assumed that the proteins undergoing enhanced degradation are of limited importance for cell viability, and can be sacrificed to support the continuing synthesis of key proteins.

Short-lived regulatory proteins are degraded in the cytosol by local proteolytic mechanisms. All short-lived proteins are thought to contain recognition signals that mark them for early degradation. One commonly employed method is the selective labelling of targeted proteins by ubiquitin molecules. Ubiquitin, a protein of 76 amino acids, binds covalently to available lysine residues on target proteins, which are then recognised by proteases. A number of molecular recognition signals for intracellular protein degradation have been identified, and there are likely to be others as yet undiscovered.

Additional degradative mechanisms exist for the identification and rapid degradation of proteins that contain translational or post-translational errors, or have been damaged in some way. The degradation of red blood cells is unusual in that it is age dependent. As a consequence haemoglobin also exhibits age-linked degradation.

Beatrice Gorinsky, 1994 
Excerpted from http://www.cryst.bbk.ac.uk/PPS95/course/1_synthesis/prot_degradation.html