Ubiquitin protein ligase

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^[1]. 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^[2]. UPL XIAP is inhibited by Smac – a death signaling protein.

For E3 ubiquitin-protein ligase parkin see Parkin.

Disease

XIAP mutations cause X-linked lymphoproliferative syndrome type 2^[3]. Parkin UPL has a direct causal role in neurodegenerative disorders^[4]. Cereblon nonsense mutation causes autosomal recessive nonsyndromic mental retardation^[5].

Relevance

Overexpression of UPL XIAP functions as tumor marker. UPL cereblon is inhibited by thalidomide^[6].

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^[7].

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For some details see

• TIR1 ubiquitin ligase
  
• Herbicide 2,4-D bound to TIR1 Ubiquitin Ligase.