SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP)

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Domagoj Vucic - , Department of Molecular Oncology, Genentech Incorporated (Autor:in)
  • Kurt Deshayes - , Genentech Incorporated, Department of Protein Engineering (Autor:in)
  • Heidi Ackerly - , Genentech Incorporated (Autor:in)
  • Maria Teresa Pisabarro - , Strukturelle Bioinformatik (FoG), Biotechnologisches Zentrum (BIOTEC), Genentech Incorporated (Autor:in)
  • Saloumeh Kadkhodayan - , Genentech Incorporated (Autor:in)
  • Wayne J Fairbrother - , Departments of Protein Engineering, Genentech Incorporated (Autor:in)
  • Vishva M Dixit - , Department of Molecular Oncology, Genentech Incorporated (Autor:in)

Abstract

Inhibitors of apoptosis (IAPs) physically interact with a variety of pro-apoptotic proteins and inhibit apoptosis induced by diverse stimuli. X-linked IAP (X-IAP) is a prototype IAP family member that inhibits several caspases, the effector proteases of apoptosis. The inhibitory activity of X-IAP is regulated by SMAC, a protein that is processed to its active form upon receipt of a death stimulus. Cleaved SMAC binds X-IAP and antagonizes its anti-apoptotic activity. Here we show that melanoma IAP (ML-IAP), a potent anti-cell death protein and caspase inhibitor, physically interacts with SMAC through its BIR (baculovirus IAP repeat) domain. In addition to binding full-length SMAC, ML-IAP BIR associates with SMAC peptides that are derived from the amino terminus of active, processed SMAC. This high affinity interaction is very specific and can be completely abolished by single amino acid mutations either in the amino terminus of active SMAC or in the BIR domain of ML-IAP. In cells expressing ML-IAP and X-IAP, SMAC coexpression or addition of SMAC peptides abrogates the ability of the IAPs to inhibit cell death. These results demonstrate the feasibility of using SMAC peptides as a way to sensitize IAP-expressing cells to pro-apoptotic stimuli such as chemotherapeutic agents.

Details

OriginalspracheEnglisch
Seiten (von - bis)12275-12279
Seitenumfang5
FachzeitschriftThe Journal of biological chemistry
Jahrgang277
Ausgabenummer14
PublikationsstatusVeröffentlicht - 18 Jan. 2002
Peer-Review-StatusJa

Externe IDs

Scopus 0037023712

Schlagworte

Schlagwörter

  • Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Apoptosis, Carrier Proteins/metabolism, Caspase 9, Caspases/metabolism, Cell Line, Complement Membrane Attack Complex, Complement System Proteins, Dose-Response Relationship, Drug, Escherichia coli/metabolism, Glycoproteins/metabolism, Humans, Immunoblotting, Inhibitor of Apoptosis Proteins, Models, Molecular, Molecular Sequence Data, Mutation, Neoplasm Proteins/metabolism, Nucleosomes/metabolism, Peptides/chemistry, Plasmids/metabolism, Precipitin Tests, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Time Factors, Transfection, Tumor Cells, Cultured