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Information about Ubiquitin

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Ribbon representation of ubiquitin.
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Molecular surface of ubiquitin.


Ubiquitin is a highly conserved small regulatory protein that is ubiquitous in eukaryotes. Ubiquitination (or Ubiquitylation) refers to the post-translational modification of a protein by the covalent attachment (via an isopeptide bond) of one or more ubiquitin monomers. The most prominent function of Ubiquitin is labeling proteins for proteasomal degradation (see: Proteasome). Beside this function ubiquitination controls the stability, function, and intracellular localization of a wide variety of proteins.

Identification

Ubiquitin (originally, Ubiquitous Immunopoietic Polypeptide) was first identified in 1975 as an 8.5 kDa protein of unknown function expressed universally in living cells. The basic functions of ubiquitin and the components of the ubiquitination pathway were elucidated in the early 1980s in groundbreaking work performed by Aaron Ciechanover, Avram Hershko and Irwin Rose for which the Nobel Prize in Chemistry was awarded in 2004.

The ubiquitylation system was initially characterised as an ATP-dependent proteolytic system present in cellular extracts. A heat-stable polypeptide present in these extracts, ATP-dependent proteolysis factor 1 (APF-1), was found to become covalently attached to the model protein substrate lysozyme in an ATP and Mg2+-dependent process. Multiple APF-1 molecules were linked to a single substrate molecule by an isopeptide linkage and conjugates were found to be rapidly degraded with the release of free APF-1. Soon after APF-1-protein conjugation was characterised, APF-1 was identified as ubiquitin. The carboxyl group of the C-terminal glycine residue of ubiquitin (Gly76) was identified as the moiety conjugated to substrate lysine residues.

The protein

Ubiquitin properties (human)
Number of residues76
Molecular mass8564.47 Da
Isoelectric point (pI)6.79
Gene namesRPS27A (UBA80, UBCEP1), UBA52 (UBCEP2), UBB, UBC


Ubiquitin is a small protein that occurs in all eukaryotic cells. Its main known function is to mark other proteins for destruction, known as proteolysis. At least four ubiquitin molecules attach to a lysine residue on the condemned protein, in a process called polyubiquitination, and the protein then moves to a proteasome, a barrel-shaped structure where the proteolysis occurs. Apparently, at least four ubiquitins are required on a substrate protein in order for the proteasome to bind and therefore degrade the substrate, though there are examples of non-ubiquitinated proteins being targeted to the proteasome. Ubiquitin can also mark transmembrane proteins (for example, receptors) for removal from membranes and fulfill several signalling roles within the cell. Monoubiquitination has been associated with targeting of membrane proteins to the lysosome, for example.

Ubiquitin consists of 76 amino acids and has a molecular mass of about 8.5 kDa. Key features include its C-terminal tail and the Lys residues. It is highly conserved among eukaryotic species: Human and yeast ubiquitin share 96 % sequence identity. The human ubiquitin sequence is: MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG

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The ubiquitylation system.

Ubiquitination (Ubiquitylation)

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Crystal structure of ubiquitin aldehyde (top right) and deubiquitinating enzyme in complex at resolution 2.3Å[1].


The process of marking a protein with ubiquitin (ubiquitylation or ubiquitination) consists of a series of steps:
  1. Activation of ubiquitin - Ubiquitin is activated in a two-step reaction by an E1 ubiquitin-activating enzyme in a process requiring ATP as an energy source. The initial step involves production of a ubiquitin-adenylate intermediate. The second step transfers ubiquitin to the E1 active site cysteine residue, with release of AMP. This step results in a thioester linkage between the C-terminal carboxyl group of ubiquitin and the E1 cysteine sulfhydryl group.
  2. Transfer of ubiquitin from E1 to the active site cysteine of a ubiquitin-conjugating enzyme E2 via a trans(thio)esterification reaction. Mammalian genomes contain 20-30 UBCs.
  3. The final step of the ubiquitylation cascade generally requires the activity of one of the hundreds of E3 ubiquitin-protein ligases (often termed simply ubiquitin ligase). E3 enzymes function as the substrate recognition modules of the system and are capable of interaction with both E2 and substrate. E3 enzymes possess one of two domains:
  4. *The HECT (Homologous to the E6-AP Carboxyl Terminus) domain
  5. *The RING domain (or the closely related U-box domain)
Transfer can occur in two ways:
:*Directly from E2, catalysed by RING domain E3s.
:*Via an E3 enzyme, catalysed by HECT domain E3s. In this case, a covalent E3-ubiquitin intermediate is formed before transfer of ubiquitin to the substrate protein.


In many cases, ubiquitin molecules are further added on to previously-conjugated ubiquitin molecules to form a polyubiquitin chain. If the chain is longer than 3 ubiquitin molecules, the tagged protein is rapidly degraded by the 26S-proteasome into small peptides (usually 3-24 amino acid residues in length). Ubiquitin moieties are cleaved off the protein by deubiquitinating enzymes and are recycled for further use.

Cell-surface transmembrane molecules that are tagged with ubiquitin are often mono-ubiquitinated, and this modification alters the subcellular localization of the protein, often targeting the protein for destruction in lysosomes.

The Anaphase-promoting complex (APC) and the SCF complex (for Skp1-Cullin-F-box protein complex) are two examples of multi-subunit E3s involved in recognition and ubiquitination of specific target proteins for degradation by the proteasome.

Disease association

Genetic disorders

  • The gene whose disruption causes Angelman syndrome, UBE3A, encodes a ubiquitin ligase (E3) enzyme termed E6-AP.
  • The gene disrupted in Von Hippel-Lindau syndrome encodes a ubiquitin E3 ligase termed the VHL tumor suppressor or VHL gene.
  • The gene disrupted in Liddle's Syndrome results in disregulation of an epithelial Na+ channel (ENaC) and causes hypertension.

Immunohistochemistry

Antibodies to ubiquitin are used in histology to identify abnormal accumulations of protein inside cells that are markers of disease. These accumulations are called inclusion bodies. Examples of such abnormal inclusions in cells are

References

1. ^ Hu, M., Li, P., Li, M., Li, W., Yao, T., Wu, J.-W., Gu, W., Cohen, R.E., Shi, Y. Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell (2002) 111, pp.1041-1054

See also

External links

Further reading

  • Essays in Biochemistry, Volume 41 (2005): The Ubiquitin-Proteasome System (Portland Press)
 •  • [ e]
Protein primary structure and posttranslational modifications
GeneralProtein biosynthesis
N-terminusAcetylation
C-terminusAmidation
LysineMethylation
CysteineDisulfide bond
Serine/ThreoninePhosphorylation
TyrosinePhosphorylation
AsparagineDeamidation
AspartateSuccinimide formation
GlutamineTransglutamination
GlutamateCarboxylation
ArginineCitrullination
ProlineHydroxylation
Proteins are large organic compounds made of amino acids arranged in a linear chain and joined together by peptide bonds between the carboxyl and amino groups of adjacent amino acid residues.
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Post-translational modification (PTM) is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis for many proteins. A protein (also called a polypeptide) is a chain of amino acids.
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Covalent bonding is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms, or between atoms and other covalent bonds.
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Isopeptide bond is a peptide bond by side chain of an amino acid. Typically this means the amino group of lysine or the carboxyl group of glutamate.

See also

  • Organic Chemistry
  • Biochemistry
  • Glutathione
  • Ubiquitin

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A monomer (from Greek mono "one" and meros "part") is a small molecule that may become chemically bonded to other monomers to form a polymer.

Examples of monomers are hydrocarbons such as the alkene and arene homologous series.
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Proteasomes are large protein complexes inside all eukaryotes and archaea, as well as in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm.[1]
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The unified atomic mass unit (u), or dalton (Da), is a small unit of mass used to express atomic and molecular masses. It is defined to be one twelfth of the mass of an unbound atom of the carbon-12 nuclide, at rest and in its ground state.
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Aaron Ciechanover (אהרון צ'חנובר) (born October 1, 1947) is an Israeli biologist, and Nobel Prize in Chemistry laureate for his discovery with Avram Hershko and Irwin Rose, of ubiquitin-mediated protein degradation.
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Avram Hershko (Hebrew: אברהם הרשקו‎, born Herskó Ferenc, 31 December 1937) is an Israeli biochemist.
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Irwin A. Rose (born 16 July 1926 in NY) is an American biologist. Along with Aaron Ciechanover and Avram Hershko, he was awarded the 2004 Nobel Prize in Chemistry for the discovery of ubiquitin-mediated protein degradation.
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Nobel Prize in Chemistry (Swedish: Nobelpriset i kemi) is awarded once a year by the Royal Swedish Academy of Sciences. It is one of the six Nobel Prizes. The first prize was awarded in 1901.
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Adenosine 5'-triphosphate (ATP) is a multifunctional nucleotide that is most important as a "molecular currency" of intracellular energy transfer. In this role, ATP transports chemical energy within cells for metabolism.
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Proteolysis is the directed degradation (digestion) of proteins by cellular enzymes called proteases or by intramolecular digestion.

Purposes

Proteolysis is used by the cell for several purposes.
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Peptides (from the Greek πεπτίδια, "small digestibles") are short polymers formed from the linking, in a defined order, of α-amino acids.
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In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate(s). The substrate binds with the enzyme's active site, and an enzyme-substrate complex is formed.
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Lysozyme is a 14.4 kilodalton enzyme (EC 3.2.1.17 ) that damages bacterial cell walls by catalyzing hydrolysis of 1,4-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in a peptidoglycan and between N-acetyl-D-glucosamine residues in chitodextrins.
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Adenosine 5'-triphosphate (ATP) is a multifunctional nucleotide that is most important as a "molecular currency" of intracellular energy transfer. In this role, ATP transports chemical energy within cells for metabolism.
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Magnesium has the symbol Mg, the atomic number 12, and an atomic mass of 24.31. Magnesium is the ninth most abundant element in the universe by mass. It constitutes about 2% of the Earth's crust by mass, and it is the third most abundant element dissolved in seawater.
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In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate(s). The substrate binds with the enzyme's active site, and an enzyme-substrate complex is formed.
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Isopeptide bond is a peptide bond by side chain of an amino acid. Typically this means the amino group of lysine or the carboxyl group of glutamate.

See also

  • Organic Chemistry
  • Biochemistry
  • Glutathione
  • Ubiquitin

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In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate(s). The substrate binds with the enzyme's active site, and an enzyme-substrate complex is formed.
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Lysine (abbreviated as Lys or K)[1] is an α-amino acid with the chemical formula HO2CCH(NH2)(CH2)4NH2.
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molecular mass (abbreviated Mr) of a substance, formerly also called molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12).
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The unified atomic mass unit (u), or dalton (Da), is a small unit of mass used to express atomic and molecular masses. It is defined to be one twelfth of the mass of an unbound atom of the carbon-12 nuclide, at rest and in its ground state.
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The isoelectric point (pI) is the pH at which a particular molecule or surface carries no net electrical charge. Amphoteric molecules called zwitterions contain both positive and negative charges depending on the functional groups present in the molecule.
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Proteins are large organic compounds made of amino acids arranged in a linear chain and joined together by peptide bonds between the carboxyl and amino groups of adjacent amino acid residues.
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Editing of this page by unregistered or newly registered users is currently disabled due to vandalism.
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