|Index to this page|
Protein degradation is as essential to the cell as protein synthesis. For example,
- to supply amino acids for fresh protein synthesis
- to remove excess enzymes
- to remove transcription factors that are no longer needed.
There are two major intracellular devices in which damaged or unneeded proteins are broken down:
- lysosomes and
Lysosomes deal primarily with
- extracellular proteins, e.g., plasma proteins, that are taken into the cell, e.g., by endocytosis
- cell-surface membrane proteins that are used in receptor-mediated endocytosis.
- the proteins (and other macromolecules) engulfed by autophagosomes.
|Link to a discussion of lysosomes.|
Proteasomes deal primarily with endogenous proteins; that is, proteins that were synthesized within the cell such as:
- transcription factors
- cyclins (which must be destroyed to prepare for the next step in the cell cycle)
- proteins encoded by viruses and other intracellular pathogens
- proteins that are folded incorrectly because
- of translation errors
- they are encoded by faulty genes
Most cases of cystic fibrosis are caused by the accelerated degradation of a mutant version of a chloride transporter. [Link]
- they have been damaged by other molecules in the cytosol.
Structure of the Proteasome
The Core Particle (CP)
- The core particle is made of 2 copies of each of 14 different proteins.
- These are assembled in groups of 7 forming a ring.
- The 4 rings are stacked on each other (like 4 doughnuts).
The Regulatory Particle (RP)
- There are two identical RPs, one at each end of the core particle.
- Each is made of 19 different proteins (none of them the same as those in the CP).
- 6 of these are ATPases.
- Some of the subunits have sites that recognize the protein ubiquitin.
- a small protein (76 amino acids);
- conserved throughout all the kingdoms of life; that is, virtually identical in sequence whether in bacteria, yeast, or mammals;
- used by all these creatures to target proteins for destruction.
Proteins destined for destruction
- are conjugated to a molecule of ubiquitin which binds to the terminal amino group of a lysine residue.
- Additional molecules of ubiquitin bind to the first forming a chain.
- The complex binds to ubiquitin-recognizing site(s) on the regulatory particle.
- The protein is unfolded by the ATPases using the energy of ATP.
- The unfolded protein is translocated into the central cavity of the core particle.
- Several active sites on the inner surface of the two middle "doughnuts" break various specific peptide bonds of the chain.
- This produces a set of peptides averaging about 8 amino acids long.
- These leave the core particle by an unknown route where
- they may be further broken down into individual amino acids by peptidases in the cytosol or
- in mammals, they may be incorporated in a class I histocompatibility molecule to be presented to the immune system as a potential antigen [see below].
- The regulatory particle releases the ubiquitins for reuse.
On 13 May 2003, the U.S. Food and Drug Administration (FDA) approved a drug called bortezomib (Velcade®) (formerly known as LDP-341) to treat patients with multiple myeloma, a cancer of plasma cells.The drug blocks the proteolytic action of the proteasome.
Antigen Processing by Proteasomes
In mammals, activation of the immune system
- leads to the release of the cytokine interferon-gamma.
- This causes three of the subunits in the core particle to be replaced by substitute subunits.
- The peptides generated in this altered proteasome are picked up by TAP (= transporter associated with antigen processing) proteins and transported from the cytosol into the endoplasmic reticulum where
- each enters the groove at the surface of a class I histocompatibility molecule.
- This complex then moves through the Golgi apparatus and is inserted in the plasma membrane where it can be "recognized" by CD8+ T cells.
|Link to a discussion of antigen presentation in the class I pathway.|
|It is probably no coincidence that the genes encoding