Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as
ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a
proteinProteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
for degradation via the
proteasomeProteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
.The ubiquitination process covalently attaches
ubiquitinUbiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
, a short protein of 76
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s, to a
lysineLysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the
ATPAdenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
-dependent
unfoldingDenaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
of the target protein that allows passage into the proteasome's 20S core particle, where
proteaseA protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s degrade the target into short
peptidePeptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
fragments for recycling by the
cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
.
Relationships
A
ubiquitin-activating enzymeUbiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which targets a protein for degradation via a proteasome. This covalent attachment of ubiquitin or ubiquitin-like proteins to targeted proteins is a major mechanism for regulating protein...
or E1 first activates the ubiquitin by covalently attaching the molecule to its
active siteIn biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
cysteineCysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residue. The activated ubiquitin is then transferred to an E2 cysteine. Once conjugated to ubiquitin, the E2 molecule binds one of several
ubiquitin ligaseA ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
s or E3s via a structurally conserved
bindingProtein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
region. The E3 molecule is responsible for binding the target protein
substrateIn biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
and transferring the ubiquitin from the E2 cysteine to a lysine residue on the target protein.
A particular cell usually contains only a few types of E1 molecule, a greater diversity of E2s, and a very large variety of E3s. The E3 molecules responsible for substrate identification and binding are thus the mechanisms of substrate specificity in proteasomal degradation. Each type of E2 can associate with many E3s.
Isozymes
The following human genes encode ubiquitin-conjugating enzymes:
- UBE2A
Ubiquitin-conjugating enzyme E2 A is a protein that in humans is encoded by the UBE2A gene.-Interactions:UBE2A has been shown to interact with RAD18 and P53.-Further reading:...
- UBE2B
Ubiquitin-conjugating enzyme E2 B is a protein that in humans is encoded by the UBE2B gene.-Further reading:...
- UBE2C
Ubiquitin-conjugating enzyme E2 C is a protein that in humans is encoded by the UBE2C gene.-Further reading:...
- UBE2D1
Ubiquitin-conjugating enzyme E2 D1 is a protein that in humans is encoded by the UBE2D1 gene.-Interactions:UBE2D1 has been shown to interact with BARD1, UBE3A and BRCA1.-Further reading:...
, UBE2D2Ubiquitin-conjugating enzyme E2 D2 is a protein that in humans is encoded by the UBE2D2 gene.-Interactions:UBE2D2 has been shown to interact with PJA1, Baculoviral IAP repeat-containing protein 3, PJA2, UBE3A and NEDD4.-Further reading:...
, UBE2D3Ubiquitin-conjugating enzyme E2 D3 is a protein that in humans is encoded by the UBE2D3 gene.-Further reading:...
, UBE2D4 (the latter putative)
- UBE2E1
Ubiquitin-conjugating enzyme E2 E1 is a protein that in humans is encoded by the UBE2E1 gene.-Interactions:UBE2E1 has been shown to interact with Ataxin 1 and NEDD4.-Further reading:...
, UBE2E2Ubiquitin-conjugating enzyme E2 E2 is a protein that in humans is encoded by the UBE2E2 gene.-Further reading:...
, UBE2E3Ubiquitin-conjugating enzyme E2 E3 is a protein that in humans is encoded by the UBE2E3 gene.-Further reading:...
- UBE2F (putative)
- UBE2G1
Ubiquitin-conjugating enzyme E2 G1 is a protein that in humans is encoded by the UBE2G1 gene.-Further reading:...
, UBE2G2Ubiquitin-conjugating enzyme E2 G2 is a protein that in humans is encoded by the UBE2G2 gene.-Further reading:...
- UBE2H
Ubiquitin-conjugating enzyme E2 H is a protein that in humans is encoded by the UBE2H gene.-Further reading:...
- UBE2I
SUMO-conjugating enzyme UBC9 is a protein that in humans is encoded by the UBE2I gene.-Interactions:UBE2I has been shown to interact with WT1, TOP1, RAD51, Activating transcription factor 2, PIAS1, SALL1, FHIT, RANBP2, Protein inhibitor of activated STAT2, DNMT3A, DNMT3B, Small ubiquitin-related...
- UBE2J1
Ubiquitin-conjugating enzyme E2 J1 is a protein that in humans is encoded by the UBE2J1 gene.-Further reading:...
, UBE2J2
- UBE2K
- UBE2L3
Ubiquitin-conjugating enzyme E2 L3 is a protein that in humans is encoded by the UBE2L3 gene.-Interactions:UBE2L3 has been shown to interact with UBOX5, ARIH1, Cbl gene, UBE3A and NEDD4.-Further reading:...
, UBE2L6Ubiquitin/ISG15-conjugating enzyme E2 L6 is a protein that in humans is encoded by the UBE2L6 gene.-Further reading:...
; (UBE2L1, UBE2L2, UBE2L4 are pseudogenes)
- UBE2M
NEDD8-conjugating enzyme Ubc12 is a protein that in humans is encoded by the UBE2M gene.-Interactions:UBE2M has been shown to interact with NEDD8, PRKAR1A and UBA3.-Further reading:...
- UBE2N
Ubiquitin-conjugating enzyme E2 N is a protein that in humans is encoded by the UBE2N gene.-Interactions:UBE2N has been shown to interact with Aurora A kinase, TRAF2, TRAF6, HLTF and UBE2V1.-Further reading:...
- UBE2O
Ubiquitin-conjugating enzyme E2 O is a protein that in humans is encoded by the UBE2O gene.-Further reading:...
- UBE2Q1, UBE2Q2
- UBE2R1 (CDC34), UBE2R2
Ubiquitin-conjugating enzyme E2 R2 is a protein that in humans is encoded by the UBE2R2 gene.-Further reading:...
- UBE2S
- UBE2T (putative)
- UBE2U (putative)
- UBE2V1
Ubiquitin-conjugating enzyme E2 variant 1 is a protein that in humans is encoded by the UBE2V1 gene.-Further reading:...
, UBE2V2Ubiquitin-conjugating enzyme E2 variant 2 is a protein that in humans is encoded by the UBE2V2 gene.-Further reading:...
- UBE2W (putative)
- UBE2Z
- ATG3
- BIRC6
Baculoviral IAP repeat-containing protein 6 is a protein that in humans is encoded by the BIRC6 gene.-Further reading:...
- UFC1