The ubiquitin-mediated proteolytic pathway

Mechanisms of recognition of the proteolytic substrate and involvement in the degradation of native cellular proteins

Aaron Ciechanover, Alan L. Schwartz

Research output: Contribution to journalReview articleResearchpeer-review

166 Citations (Scopus)

Abstract

Ubiquitin modification of a variety of protein targets within the cell plays important roles in many cellular processes. Among these are regulation of gene expression, regulation of cell cycle and division, involvement in the cellular stress response, modification of cell surface receptors, DNA repair, import of proteins into mitochondria, uptake of precursors into neurons, and biogenesis of mitochondria, ribosomes, and peroxisomes. The best studied modification occurs in the ubiquitin-mediated proteolytic pathway. Degradation of a protein via the ubiquitin system involves two discrete steps. Initially, multiple ubiquitin molecules are covalently linked in an ATP-dependent mode to the protein substrate. The targeted protein is then degraded by a specific and energy-dependent high molecular mass protease into free amino acids, and free and reutilizable ubiquitin is released. In addition, stable mono-ubiquitin adducts are also found in the cell, for example, those involving nucleosomal histones. Despite the considerable progress that has been made in elucidating the mode of action and roles of the ubiquitin system, many problems remain unsolved. For example, little is known on the signals that target proteins for degradation. Although mechanistic aspects of recognition via the N-terminal residue have been studied thoroughly, it is clear that the vast majority of cellular proteins are targeted by other signals. The identity of the native cellular substrates of the system is another important, yet unresolved, problem: only few proteins have been recognized so far as substrates of the system in vivo. The scope of this review is to discuss the mechanisms involved in ubiquitin activation, selection of substrates for conjugation, and degradation of ubiquitin-conjugated proteins in the cell-free system. In addition, we shall summarize what is currently known of the physiological roles of ubiquitin- mediated proteolysis in vivo.

Original languageEnglish
Pages (from-to)182-191
Number of pages10
JournalFASEB Journal
Volume8
Issue number2
StatePublished - 11 Mar 1994

Fingerprint

Ubiquitin
Degradation
Substrates
Proteins
Proteolysis
Mitochondria
Gene Expression Regulation
Gene expression regulation
Peroxisomes
Cell-Free System
Cell Surface Receptors
Molecular mass
Ribosomes
DNA Repair
Histones
Neurons
Cell Cycle
Repair
Peptide Hydrolases
Adenosine Triphosphate

Keywords

  • 26S protease complex
  • ATP
  • energy dependence
  • MCP (multicatalytic proteinase complex, proteasome)
  • N-α-acetylated proteins
  • protein degradation
  • ubiquitin

Cite this

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The ubiquitin-mediated proteolytic pathway : Mechanisms of recognition of the proteolytic substrate and involvement in the degradation of native cellular proteins. / Ciechanover, Aaron; Schwartz, Alan L.

In: FASEB Journal, Vol. 8, No. 2, 11.03.1994, p. 182-191.

Research output: Contribution to journalReview articleResearchpeer-review

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