Protein Degradation and Turnover


The protein constituents of an organism and its cells are continuously being synthesized and degraded (turned over). Protein degradation is essential for recycling of amino acids, removal of damaged or misfolded proteins and controlling a variety of fundamental biological processes.

Keywords: lysosome; ubiquitin; proteasome; protease; ATPase; disease

Figure 1.

Pathways of protein breakdown in mammalian cells. Most cytosolic and nuclear proteins in mammalian cells are broken down by the ubiquitin–proteasome pathway and some peptide products are utilized for MHC class I antigen presentation. The same pathway also mediates degradation of endoplasmic reticulum (ER) proteins (both integral membrane and luminal proteins) in the process called (ERAD). Some mitochondrial proteins are broken down by their own ATP‐dependent proteases. Extracellular and autophagocytized proteins and most membrane proteins are broken down within the lysosome–endosomal compartment, which provides peptides for MHC class II antigen presentation. Exceptions (as indicated by dashed lines) are some membrane proteins that are broken down by the ubiquitin–proteasome pathway, and some cytosolic proteins that are degraded in lysosomes.

Figure 2.

Ubiquitin–proteasome pathway. Protein substrate destined for degradation by the 26S proteasome is first conjugated to multiple molecules of Ubiquitin in a series of reactions involving ubiquitin‐activating enzyme, E1, ubiquitin‐carrier protein, E2, and ubiquitin‐protein ligase, E3. Polyubiquitinated substrates are rapidly hydrolyzed by the 26S proteasome, and monomeric Ubiquitin is recycled by the action of deubiquitinating enzymes. The energy of ATP is required for Ubiquitin conjugation, unfolding of a substrate and its translocation into the inner cavities of the proteasome. Most peptides produced by proteasomes are further degraded to amino acids by endo‐ and exopeptidases in the cytosol and nucleus, but a small fraction of peptides escapes complete hydrolysis and are utilized for MHC class I antigen presentation.

Figure 3.

Ubiquitin‐conjugation cascade. The Ubiquitin is first activated by the ubiquitin‐activating enzyme, E1, in an ATP‐dependent reaction. In the second reaction, Ubiquitin is transferred to the ubiquitin‐carrier protein, E2. The resultant high‐energy E2∼ubiquitin thioester intermediate mediates conjugation of activated Ubiquitin to the protein substrate in the presence of a ubiquitin‐protein ligase, E3. New Ubiquitin moieties are linked to the previously bound Ubiquitin in successive rounds of conjugation.



Bryant PW, Lennon‐Dumenil AM, Fiebiger E, Lagaudriere‐Gesbert C and Ploegh HL (2002) Proteolysis and antigen presentation by MHC class II molecules. Advances in Immunology 80: 71–114.

Etlinger JD and Goldberg AL (1977) A soluble ATP‐dependent proteolytic system responsible for the degradation of abnormal proteins in reticulocytes. Proceedings of the National Academy of Sciences of the United States of America 74: 54–58.

Glickman MH and Ciechanover A (2002) The ubiquitin‐proteasome proteolytic pathway: destruction for the sake of construction. Physiological Reviews 82: 373–428.

Goldberg AL and St John AC (1976) Intracellular protein degradation in mammalian and bacterial cells: part 2. Annual Reviews in Biochemistry 45: 747–803.

Hicke L (2001) Protein regulation by monoubiquitin. Nature Reviews Molecular Cell Biology 2: 195–201.

Hough R, Pratt G and Rechsteiner M (1987) Purification of two molecular weight proteases from rabbit reticulocyte lysate. Journal of Biological Chemistry 262: 8303–8313.

Kisselev AF and Goldberg AL (2001) Proteasome inhibitors: from research tools to drug candidates. Chemistry and Biology 8: 739–758.

Kisselev AF, Akopian TN, Woo KM and Goldberg AL (1999) The sizes of peptides generated from protein by mammalian 26 and 20 S proteasomes. Implications for understanding the degradative mechanism and antigen presentation. Journal of Biological Chemistry 274: 3363–3371.

Navon A and Goldberg AL (2001) Proteins are unfolded on the surface of the ATPase ring before transport into the proteasome. Molecular Cell 8: 1339–1349.

Schmidt M, Lupas AN and Finley D (1999) Structure and mechanism of ATP‐dependent proteases. Current Opinion in Chemical Biology 3: 584–591.

Voges D, Zwickl P and Baumeister W (1999) The 26S proteasome: a molecular machine designed for controlled proteolysis. Annual Reviews in Biochemistry 68: 1015–1068.

Waxman L, Fagan JM and Goldberg AL (1987) Demonstration of two distinct high molecular weight proteases in rabbit reticulocytes, one of which degrades Ubiquitin conjugates. Journal of Biological Chemistry 262: 2451–2457.

Further Reading

Adams J (2002) Proteasome inhibition: a novel approach to cancer therapy. Trends in Molecular Medicine 8: S49–S54.

Benaroudj N, Tarcsa E, Cascio P and Goldberg AL (2001) The unfolding of substrates and ubiquitin‐independent protein degradation by proteasomes. Biochimie 83: 311–318.

Cuervo AM and Dice JF (1998) Lysosomes, a meeting point of proteins, chaperones, and proteases. Journal of Molecular Medicine 76: 6–12.

Goldberg AL, Cascio P, Saric T and Rock K (2002) The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides. Molecular Immunology 39: 147.

Hampton R (2002) ER‐associated degradation in protein quality control and cellular regulation. Current Opinions in Cell Biology 14: 476–482.

Hershko A (1996) Lessons from the discovery of the Ubiquitin system. Trends in Biochemical Sciences 21: 445–449.

Jentsch S and Pyrowolakis G (2000) Ubiquitin and its kin: how close are the family ties? Trends in Cell Biology 10: 335–342.

Käser M and Langer T (2000) Protein degradation in mitochondria. Seminars in Cell and Developmental Biology 11: 181–190.

Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends in Cell Biology 10: 524–530.

Peters JM, Harris JR and Finley D (1998) Ubiquitin and the Biology of the Cell. New York/London: Plenum Press.

Reboud‐Ravaux M (2002) Protein Degradation in Health and Disease. Berlin/Heidelberg/New York: Springer Verlag.

Rock KL, York IA, Saric T and Goldberg AL (2002) Protein degradation and the generation of MHC class I‐presented peptides. Advances in Immunology 80: 1–70.

Weissman AM (2001) Themes and variations on ubiquitylation. Nature Reviews Molecular Cell Biology 2: 169–178.

Wilkinson KD (2000) Ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome. Seminars in Cell and Developmental Biology 11: 141–148.

Yewdell J (2002) To DRiP or not to DRiP: generating peptide ligands for MHC class I molecules from biosynthesized proteins. Molecular Immunology 39: 139.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Saric, Tomo, and Goldberg, Alfred L(Jan 2006) Protein Degradation and Turnover. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0005722]