Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination.
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.
Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Erin C
EC
Dueber
Allyn J
AJ
Schoeffler
Andreas
A
Lingel
J Michael
JM
Elliott
Anna V
AV
Fedorova
Anthony M
AM
Giannetti
Kerry
K
Zobel
Brigitte
B
Maurer
Eugene
E
Varfolomeev
Ping
P
Wu
Heidi J A
HJ
Wallweber
Sarah G
SG
Hymowitz
Kurt
K
Deshayes
Domagoj
D
Vucic
Wayne J
WJ
Fairbrother
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D053838:Scattering, Small Angle; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000737:chemistry / Q000378:metabolism; D054875:Ubiquitination
D051034:Inhibitor of Apoptosis Proteins; D057149:Ubiquitinated Proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex