All proteins are eventually destroyed by hydrolysis; this accounts for the fact that proteins in fossils cannot last forever. But hydrolysis is slow unless it is catalyzed by proteases, and in general proteases cannot discriminate between proteins that are damaged or no longer needed in the cell and those that are vital. Therefore, there must be pathways that can mark and then destroy some proteins while not affecting others. Such pathways are known and play vital roles in the cell.
The proteasome is the general protein destruction system
The proteasome is responsible for the degradation of hundreds, possibly thousands, of badly misfolded or otherwise aberrant (mutated) proteins. It also destroys regulatory proteins, such as transcription factors or cell-cycle regulators, that must be available within a cell for strictly regulated brief periods and need to be destroyed once they have performed their function. Thus, transcription factors that regulate the expression of genes in response to temporary stimuli are needed only over a short period of time, and cyclins, the proteins that regulate the progression of the cell through the cell cycle, need to be present only during specific phases of the cycle and then must be degraded to allow the cell to move to the next phase.
Proteins that are destined for degradation by the proteasome will be marked by the covalent attachment of chains of the small protein molecule ubiquitin. The structural feature recognized by the ubiquitylation system is thought to be the presence of stable patches of hydrophobic amino acid residues exposed on the surface of the misfolded chain. These are not present on proteins with normal tertiary structure; rather, such residues are usually buried within the protein. Their presence on the surface indicates that something is wrong. This ubiquitylation “kiss of death” leads the marked protein to a multisubunit structure called the proteasome.
The proteasome degradation process is shown schematically in Figure 1A. The eukaryotic proteasome consists of a 20S core particle formed by four heptameric rings, two outer α-rings and two inner β-rings (Figure 1B and Figure 1C), and one or two 19S regulatory particles of very complex composition. Some of the proteins in the core particle possess activities that hydrolytically degrade the client proteins. The main function of the 19S regulatory particle is to first recognize the ubiquitylated protein and then regulate access of the client protein to the 20S degradation chamber. The opening to this chamber is tiny, only 1.3 nm in diameter, and only unfolded polypeptide chains can pass through it. Thus, access to the degradation chamber is regulated by the 19S particle first unfolding the client proteins. In addition, specific proteins in the 19S complex act as ubiquitin receptors, whereas others function to remove the polyubiquitin chains once the client protein is recognized and bound.
Fig1. The proteasome: Structure and protein degradation. (A) Left, proteins to be degraded by the proteasome are usually modified by polyubiquitin chains, which are recognized and bound by components of the 19S regulatory particle of the proteasome. The misfolded protein needs to be unfolded to pass through the narrow gate of the 20S core particle of the proteasome. Right, cross-section of the proteasome in action. (B) Left, schematic of subunit structure of the 26S proteasome. RP, regulatory particle, consisting of base and lid components; Rpn, regulatory particle non-ATPases; Rpt, regulatory particle ATPases. Right, three-dimensional reconstitution of the proteasome from single particles visualized by electron microscopy. (C) Left, architecture of the 20S core particle from yeast, ribbon diagram. Middle, volume of the particle calculated from atomic coordinates, cut in half to show three chambers within the particle. Right, top surface of the α-ring: the N-termini of the individual subunits form a closed gate that blocks access to the inner chamber. [A, left, adapted from Hochstrasser M (2009) Nature 458: 422–429. With permission from Macmillan Publishers, Ltd. A, right, from Wikimedia. B, left, adapted from Tanaka K (2009) Proc Jpn Acad Ser B 85: 12–36. With permission from The Japan Academy. B, right, from Lasker K, Förster F, Bohn S et al. (2012) Proc Natl Acad Sci USA 109: 1380–1387. With permission from National Academy of Sciences. C, from Cheng Y (2009) Curr Opin Struct Biol 19: 203–208. With permission from Elsevier.]
