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Encyclopedia > Ubiquitin

Ubiquitin is a very 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. 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. A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Kingdoms Eukaryotes are organisms with complex cells, in which the genetic material is organized into membrane-bound nuclei. ... Posttranslational modification means the chemical modification of a protein after its translation. ... Covalent bonding is a form of chemical bonding characterized by the sharing of one or more pairs of electrons between atoms, in order to produce a mutual attraction, which holds the resultant molecule together. ... Figure 1: Locations of the epsilon Nitrogen, isopeptide bond, and peptide bond. ... In chemistry, 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. ... Possible meanings: Kachin Defense Army Kentucky Distillers Association Kongsberg Defence & Aerospace This page expands a three-character combination which might be any or all of: an abbreviation, an acronym, an initialism, a word in English, or a word in another language. ... Aaron Ciechanover (אהרון צחנובר) (born October 1, 1947) is an Israeli biologist. ... Avram Hershko (born December 31, 1937) is an Israeli biologist. ... Irwin A. Rose (born 16 July 1926 in NY) is an American biologist. ... This is a list of Nobel Prize laureates in Chemistry from 1901 to 2006. ... 2004 (MMIV) was a leap year starting on Thursday of the Gregorian calendar. ...


Poly-ubiquitination, the process in which a chain of at least four ubiquitin peptides are attached to a lysine on a substrate protein, most commonly results in the degradation of the substrate protein via the proteasome. 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). A proteasome is a barrel-shaped multi-protein complex that can digest other proteins into short polypeptides and amino acids in an ATP-driven reaction. ...


Mono-ubiquitination, the process in which a single ubiquitin peptide is bound to a substrate, initiates cell signaling by allowing other proteins that contain ubiquitin binding domains to interact with the mono-ubiquitinated substrate. Mono-ubiquitination has been associated with targeting of membrane proteins to the lysosome, for example.


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. Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... Peptides (from the Greek πεπτος, digestible), are the family of short molecules formed from the linking, in a defined order, of various α-amino acids. ... In biochemistry, a substrate is a molecule upon which an enzyme acts. ... Lysozyme 3D structure. ... Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... General Name, Symbol, Number magnesium, Mg, 12 Chemical series alkaline earth metals Group, Period, Block 2, 3, s Appearance silvery white Atomic mass 24. ... In biochemistry, a substrate is a molecule upon which an enzyme acts. ... In biochemistry, a substrate is a molecule upon which an enzyme acts. ... Lysine is one of the 20 amino acids normally found in proteins. ...

Contents

The protein

Ubiquitin properties (human)
Number of residues 76
Molecular mass 8564.47 Da
Isoelectric point (pI) 6.79
Gene names RPS27A (UBA80, UBCEP1), UBA52 (UBCEP2), UBB, UBC

Ubiquitin is a small protein that occurs in all eukaryotic cells. Its main function is to mark other proteins for destruction, known as proteolysis. Several ubiquitin molecules attach to the condemned protein (polyubiquitination), and it then moves to a proteasome, a barrel-shaped structure where the proteolysis occurs. Ubiquitin can also mark transmembrane proteins (for example, receptors) for removal from membranes and fulfill several signalling roles within the cell. The key features of the ubiquitin protein are its C-terminal tail and the Lys residues. The molecular mass (abbreviated MM) 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). ... The unified atomic mass unit (u), or dalton (Da), is a small unit of mass used to express atomic masses and molecular masses. ... The isoelectric point sucks (pI) is the pH at which a molecule carries no net electrical charge. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Kingdoms Animalia - Animals Fungi Plantae - Plants Protista Alternative Phylogeny Unikonta    Opisthokonta    Amoebozoa Bikonta    Apusozoa    Cabozoa       Rhizaria       Excavata    Corticata       Archaeplastida       Chromalveolata Animals, plants, fungi, and protists are eukaryotes (IPA: ), organisms with a complex cell or cells, where the genetic material is organized into a membrane-bound nucleus or nuclei. ... Drawing of the structure of cork as it appeared under the microscope to Robert Hooke from Micrographia which is the origin of the word cell. Cells in culture, stained for keratin (red) and DNA (green). ... Proteolysis is the directed degradation (digestion) of proteins by cellular enzymes called proteases or by intramolecular digestion. ... A proteasome is a barrel-shaped multi-protein complex that can digest other proteins into short polypeptides and amino acids in an ATP-driven reaction. ... A transmembrane protein is a protein that spans the entire biological membrane. ... In biochemistry, a receptor is a protein on the cell membrane or within the cytoplasm or cell nucleus that binds to a specific molecule (a ligand), such as a neurotransmitter, hormone, or other substance, and initiates the cellular response to the ligand. ... A biological membrane or biomembrane is an enclosing or separating tissue which acts as a barrier within or around a cell. ... Lysine is one of the 20 amino acids normally found in proteins. ...


Ubiquitin consists of 76 amino acids and has a molecular mass of about 8500 Da. It is highly conserved among eukaryotic species: Human and yeast ubiquitin share 96 % sequence identity. The human ubiquitin sequence is: Phenylalanine is one of the standard amino acids. ... The molecular mass (abbreviated MM) 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). ... The unified atomic mass unit (u), or dalton (Da), is a small unit of mass used to express atomic masses and molecular masses. ... Sequence alignment is an arrangement of two or several biological sequences (e. ...

 MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG 
Ribbon representation of ubiquitin.
Ribbon representation of ubiquitin.
Molecular surface of ubiquitin.
Molecular surface of ubiquitin.
The ubiquitylation system.
The ubiquitylation system.

Image File history File links Download high resolution version (828x575, 152 KB)Cartoon representation of ubiquitin protein, highlighting the secondary structure. ... Image File history File links Download high resolution version (828x575, 152 KB)Cartoon representation of ubiquitin protein, highlighting the secondary structure. ... Image File history File links Download high resolution version (942x673, 395 KB)Molecular surface representation of the ubiquitin protein coloured in violet. ... Image File history File links Download high resolution version (942x673, 395 KB)Molecular surface representation of the ubiquitin protein coloured in violet. ... Image File history File links Ubiquitylation. ... Image File history File links Ubiquitylation. ...

Ubiquitylation

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:
    • The HECT (Homologous to the E6-AP Carboxyl Terminus) domain
    • 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. Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... The active site of an enzyme is the binding site where catalysis occurs. ... Cysteine is a naturally occurring amino acid which has a thiol group and is found in most proteins, though only in small quantities. ... Adenosine monophosphate, also known as 5-adenylic acid and abbreviated AMP, is a nucleotide that is found in RNA. It is an ester of phosphoric acid with the nucleoside adenosine. ... Sulfhydryl // In organic chemistry, a thiol is a compound that contains the functional group composed of a sulfur atom and a hydrogen atom (-SH). ... The active site of an enzyme is the binding site where catalysis occurs. ... In biochemistry, a substrate is a molecule upon which an enzyme acts. ... In biochemistry, a substrate is a molecule upon which an enzyme acts. ... --RAG 01:54, 16 March 2007 (UTC) The concept of the domain was first proposed in 1973 by Wetlaufer after X-ray crystallographic studies of hen lysozyme (Phillips, 1966), papain (Drenth et al. ... A proteasome is a barrel-shaped multi-protein complex that can digest other proteins into short polypeptides and amino acids in an ATP-driven reaction. ... Peptides (from the Greek πεπτος, digestible), are the family of short molecules formed from the linking, in a defined order, of various α-amino acids. ... Phenylalanine is one of the standard amino acids. ...


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 ubiquitin pathway is thought to be the method of cellular egress for a number of retroviruses, including HIV and Ebola, but the exact mechanism by which this occurs has yet to be deduced. Genera Alpharetrovirus Betaretrovirus Gammaretrovirus Deltaretrovirus Epsilonretrovirus Lentivirus Spumavirus A retrovirus is a virus which has a genome consisting of two identical plus sense RNA molecules. ... Species Human immunodeficiency virus 1 Human immunodeficiency virus 2 Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS, a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. ... Ebola is the common term for a group of viruses belonging to genus Ebolavirus, family Filoviridae, which cause Ebola hemorrhagic fever. ...


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. Anaphase-promoting complex (APC) is a complex of several proteins which is activated during mitosis to initiate anaphase. ... The introduction to this article provides insufficient context for those unfamiliar with the subject matter. ... In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles (or coassembles) with other protein molecules to form a multimeric or oligomeric protein. ... A proteasome is a barrel-shaped multi-protein complex that can digest other proteins into short polypeptides and amino acids in an ATP-driven reaction. ...


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.

A genetic disorder or a clinical phenotype. ... Angelman Syndrome (AS) is a rare neuro-genetic disorder named after an English pediatrician, Dr. Harry Angelman, who first described the syndrome in 1965. ... Von Hippel-Lindau disease (VHL) is a rare inherited genetic condition involving the abnormal growth of tumors in parts of the body which are particularly rich in blood supply. ... Liddles Syndrome is an autosomal dominant disorder that mimics hyperaldosteronism. ...

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 Immunohistochemistry or IHC refers to the process of localizing proteins in cells of a tissue section exploiting the principle of antibodies binding specifically to antigens in biological tissues. ... Schematic of antibody binding to an antigen An antibody or immunoglobulin is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses. ... A thin section of lung tissue stained with hematoxylin and eosin. ...

Neurofibrillary tangles are pathological protein aggregates found within neurons in cases of Alzheimers disease. ... Lewy bodies are abnormal aggregates of protein that develop inside nerve cells. ... Pick bodies are silver-staining, spherical aggregations of tau protein in neurons associated with Picks disease. ... Picks disease is a dementing illness associated with deterioration of the frontal and temporal lobes of the brain. ... Motor neuron disease (MND) is a term used to cover a number of illnesses of the motor neurone; amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), progressive bulbar palsy (PBP), and primary lateral sclerosis (PLS) are all forms of MND. MND is the term used internationally... Astrocytes, also known as astroglia, are characteristic star-shaped glial cells in the brain. ...

External links

Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ...

Further reading

  • Essays in Biochemistry, Volume 41 (2005): The Ubiquitin-Proteasome System (Portland Press)


Protein primary structure and posttranslational modifications
General: Protein biosynthesis | Peptide bond | Proteolysis | Racemization | N-O acyl shift
N-terminus: Acetylation | Formylation | Myristoylation | Pyroglutamate | methylation | glycation | myristoylation (Gly) | carbamylation
C-terminus: Amidation | Glycosyl phosphatidylinositol (GPI) | O-methylation | glypiation | ubiquitination | sumoylation
Lysine: Methylation | Acetylation | Acylation | Hydroxylation | Ubiquitination | SUMOylation | Desmosine | deamination and oxidation to aldehyde| O-glycosylation | imine formation | glycation | carbamylation
Cysteine: Disulfide bond | Prenylation | Palmitoylation
Serine/Threonine: Phosphorylation | Glycosylation
Tyrosine: Phosphorylation | Sulfation | porphyrin ring linkage | flavin linkage | GFP prosthetic group (Thr-Tyr-Gly sequence) formation | Lysine tyrosine quinone (LTQ) formation | Topaquinone (TPQ) formation
Asparagine: Deamidation | Glycosylation
Aspartate: Succinimide formation
Glutamine: Transglutamination
Glutamate: Carboxylation | polyglutamylation | polyglycylation
Arginine: Citrullination | Methylation
Proline: Hydroxylation
←Amino acids Secondary structure→

  Results from FactBites:
 
Definition of Ubiquitin (318 words)
Several ubiquitin molecules attach to the condemned protein, and it...
1:...ypically involved in polyubiquitylation: a second ubiquitin is attached to the first, a third is attached to...
The APC is a [[ubiquitin ligase]] that marks target proteins for degradati...
Parkinson's disease - Wikipedia, the free encyclopedia (6881 words)
PARK3 (OMIM %602404), mapped to 2p, autosomal dominant, only described in a few kindreds.
PARK5, caused by mutations in the UCHL1 gene (OMIM +191342) which codes for the protein ubiquitin carboxy-terminal hydrolase L1
PARK6 (OMIM #605909), caused by mutations in PINK1 (OMIM *608309) which codes for the protein PTEN-induced putative kinase 1.
  More results at FactBites »

 
 

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