Literature summary for 2.3.2.25 extracted from

Stewart, M.D.; Ritterhoff, T.; Klevit, R.E.; Brzovic, P.S.
E2 enzymes more than just middle men (2016), Cell Res., 26, 423-440 .

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Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [acceptor protein]-N-terminal-amino acid	Homo sapiens	-	[E1 ubiquitin-activating enzyme]-L-cysteine + N-terminal-ubiquitinyl-[acceptor protein]	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q96B02	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
additional information	the enzyme UBE2W is specific for N-terminal amine group, it interacts with E3 ligase of type RING, HECT, and RBR. Ube2W exhibits no intrinsic activity towards free lysine. Instead, Ube2W attaches Ub to the N-terminal alpha-amino group of proteins to form a Ub-fusion protein product.While still an aminolysis reaction and therefore not fundamentally different from the reaction with lysine, intrinsic reactivity assays revealed that Ube2W can transfer Ub to the alpha-amino group of small lysine-less peptides but not to free lysine. The preference for N-terminal modification by Ube2W may not be absolute, as the retroviral restriction RING E3 TRIM5alpha is monoubiquitylated by Ube2W despite being acetylated on its N-terminus. Ube2W may also facilitate isopeptide bond formation, possibly if an N-terminus is blocked. Nevertheless, the preference of Ube2W for disordered N-termini gives it a (so far) unique target selection mechanism for a primary modification event that can subsequently be exploited by other E2 enzymes to form Ub chains. The E2 Ube2W shows unique ability to monoubiquitylate proteins on their N-termini. Ube2W appears to monoubiquitylate the RING E3 ligases TRIM5alpha and TRIM21, a prerequisite for their K63 polyubiquitylation by Ube2N/Ube2V2	Homo sapiens	?	-	-
S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [acceptor protein]-N-terminal-amino acid	-	Homo sapiens	[E1 ubiquitin-activating enzyme]-L-cysteine + N-terminal-ubiquitinyl-[acceptor protein]	-	?

Subunits

Subunits	Comment	Organism
More	UBE2W shows the UBC domain organization	Homo sapiens

Synonyms

Synonyms	Comment	Organism
Ubc16	-	Homo sapiens
UBE2W	-	Homo sapiens
ubiquitin-conjugating enzyme E2	-	Homo sapiens

General Information

General Information	Comment	Organism
evolution	humans have about 40 E2s that are involved in the transfer of Ub or Ub-like (Ubl) proteins (e.g. SUMO and NEDD8). Common functional and structural features that define unifying themes among E2s, overview. Highly specific chain builders such as Ube2N, Ube2S, and Ube2R1 can only transfer their conjugated Ub to another Ub molecule. This leads to a division of labor among E2s in which one E2 initiates or primes chain synthesis and a second E2 builds and extends the polyUb chain. Ube2W is fundamentally different in its reactivity (and therefore, its substrates) from all other characterized E2s. Along with its unique reactivity profile, Ube2W has an unusual UBC domain	Homo sapiens
metabolism	ubiquitin-conjugating enzymes (E2s) are the central players in the trio of enzymes responsible for the attachment of ubiquitin (Ub) to cellular proteins. E2 regulation mechanisms, overview	Homo sapiens
additional information	E2 structure-function analysis, overview. Ube2W recognizes and modifies disordered N-termini independently of substrate sequence through interactions between its own disordered C-terminal region and the substrate backbone. The requirement of a disordered N-terminus on its substrate explains the strict monoubiquitylating activity of Ube2W, as the N-terminus of Ub is highly structured and is therefore not a good substrate for Ube2W	Homo sapiens
physiological function	humans have about 40 E2s that are involved in the transfer of Ub or Ub-like (Ubl) proteins (e.g. SUMO and NEDD8). Although the majority of E2s are only twice the size of Ub, this remarkable family of enzymes performs a variety of functional roles. Ube2W exhibits no intrinsic activity towards free lysine. Instead, Ube2W attaches Ub to the N-terminal alpha-amino group of proteins to form a Ub-fusion protein product. While still an aminolysis reaction and therefore not fundamentally differ not from the reaction with lysine, intrinsic reactivity assays revealed that Ube2W can transfer Ub to the alpha-amino group of small lysine-less peptides but not to free lysine. This feature distinguishes Ube2W as fundamentally different in its reactivity (and therefore, its substrates) from all other characterized E2s. Along with its unique reactivity profile, Ube2W has an unusual UBC domain. Ube2W recognizes and modifies disordered N-termini independently of substrate sequence through interactions between its own disordered C-terminal region and the substrate backbone. The requirement of a disordered N-terminus on its substrate explains the strict monoubiquitylating activity of Ube2W, as the N-terminus of Ub is highly structured and is therefore not a good substrate for Ube2W. The preference for N-terminal modification by Ube2W may not be absolute, as the retroviral restriction RING E3 TRIM5alpha is monoubiquitylated by Ube2W despite being acetylated on its N-terminus. Ube2W may also facilitate isopeptide bond formation, possibly if an N-terminus is blocked. Nevertheless, the preference of Ube2W for disordered N-termini gives it a (so far) unique target selection mechanism for a primary modification event that can subsequently be exploited by other E2 enzymes to form Ub chains. Ube2W may work as a chain-initiating E2 in the innate immune response where K63-linked chains play a critical role	Homo sapiens

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Release 2023.1 (January 2023)