Ubiquitin protein ligase

spinqualitylabelsall models Human UPL HOIP (magenta) complex with ubiquitin (green), imidazole and Zn+2 ion (grey) 4ljo Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Function Ubiquitin-protein ligase (UPL) (E3) or E3 ubiquitin-protein ligase in combination with ubiquitin-conjugating enzyme (E2) causes the attachment of ubiquitin to lysine in a target protein. UPL XIAP or X-linked Inhibitor of Apoptosis Protein stops apoptosis induced by viral infection or by overproduction of caspases. UPL XIAP binds caspase-3, -7 and -9. UPL XIAP is inhibited by Smac – a death signaling protein. RING-type E3 ubiquitin transferase are E3s which do not have Zn+2 coordination. HOIL-1 or RanBP-type and C3HC4-type zinc finger-containing protein 1 is an atypical E3 ligase which forms ester bonds between ubiquitin and Ser/Thr residues in proteins. NEDD4-like Ubiquitin protein ligase WWP see WWP2. Examples of E3 ubiquitin-protein ligases include Parkin Disease XIAP mutations cause X-linked lymphoproliferative syndrome type 2. Parkin UPL has a direct causal role in neurodegenerative disorders. Cereblon nonsense mutation causes autosomal recessive nonsyndromic mental retardation. Relevance Overexpression of UPL XIAP functions as tumor marker. UPL cereblon is inhibited by thalidomide and Lenalidomide. Structural highlights UPL can contain several distinct domains like: WW domains which contain 2 tryptophans which bind proline-rich peptide; UBA – Ubiquitin-Associated Domain; TKB – Tyrosine Kinase Binding domain; C2 – an 8 β strand domain which coordinates targeting proteins toward cell membrane; Cereblon is a target for thalidomide; HECT – Homologous to the E6-AP C-terminus; RING – Really Intersting New Gene involved in binding to E2; FHA – Forkhead Associated domain recognizing phosphothreonine; IBR – involved in binding to E2; PHD finger – Plant Homeo Domain is 50-80 amino acid long which contains a CHC motif; SRA – SET and RING-Associated domain; TUDOR – a ca. 50 amino acids long and recognizes dimethylated arginine; CPH – protein-protein interaction domain; UBR – a ca. 70 amino acid long zinc finger-like domain; CUE – a ubiquitin-binding domain. UPL XIAP consists of 3 BIR (baculoviral IAP repeat) domains, followed by UBA (ubiquitin-binding) domain and RING (C-terminal RING finger) domain. BIR2 inhibits caspase-3 and -7. BIR3 inhibits caspase-9. UPL contains an thioester-forming cysteine which catalyzes the transfer of ubiquitin from E2 to a substrate lysine. The surface interacting residues of UPL and the acceptor ubiquitin are shown here. Ubiquitin/protein ligase interface shown in space-filled representation. Ubiquitin/protein ligase interface interactions. 1st Zn coordination site. 2nd Zn coordination site. 3rd Zn coordination site. 4th Zn coordination site. For some details see TIR1 ubiquitin ligase Herbicide 2,4-D bound to TIR1 Ubiquitin Ligase. 3D Structures of ubiquitin protein ligase Ubiquitin protein ligase 3D structures

References

+ phosphoubiquitin

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Michal Harel, Alexander Berchansky, Tihitina Y Aytenfisu, Joel L. Sussman