Abstract
Inhibitor of apoptosis (IAP) proteins are negative regulators of cell death. IAP family members contain RING domains that impart E3 ubiquitin ligase activity. Binding of endogenous or small-molecule antagonists to select baculovirus IAP repeat (BIR) domains within cellular IAP (cIAP) proteins promotes autoubiquitination and proteasomal degradation and so releases inhibition of apoptosis mediated by cIAP. Although the molecular details of antagonist-BIR domain interactions are well understood, it is not clear how this binding event influences the activity of the RING domain. Here biochemical and structural studies reveal that the unliganded, multidomain cIAP1 sequesters the RING domain within a compact, monomeric structure that prevents RING dimerization. Antagonist binding induces conformational rearrangements that enable RING dimerization and formation of the active E3 ligase.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Cell Line
-
Cell Line, Tumor
-
Cloning, Molecular
-
Humans
-
Hydrophobic and Hydrophilic Interactions
-
Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
-
Inhibitor of Apoptosis Proteins / chemistry*
-
Inhibitor of Apoptosis Proteins / metabolism
-
Mice
-
Models, Biological
-
Models, Molecular
-
Molecular Sequence Data
-
Mutagenesis, Site-Directed
-
Proteasome Endopeptidase Complex / metabolism
-
Protein Conformation
-
Protein Interaction Domains and Motifs
-
Protein Multimerization
-
Protein Structure, Secondary
-
Scattering, Small Angle
-
Ubiquitin-Protein Ligases / chemistry
-
Ubiquitin-Protein Ligases / metabolism
-
Ubiquitinated Proteins / chemistry
-
Ubiquitinated Proteins / metabolism
-
Ubiquitination
Substances
-
Inhibitor of Apoptosis Proteins
-
Ubiquitinated Proteins
-
Ubiquitin-Protein Ligases
-
Proteasome Endopeptidase Complex