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Human baculoviral inhibitor of apoptosis repeat-containing protein 1 (BIRC1), BIR2 domain

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PDB Code 2VM5 Target Class Apoptosis Target BIRC1 Alias n/a Disease Area/Function cancer, signalling, neurobiology Date Deposited Jan 23 2008 Authors M.D.HERMAN, M.WELIN, L.LEHTIO, C.H.ARROWSMITH, H.BERGLUND, R.D.BUSAM, R.COLLINS, L.G.DAHLGREN, A.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, I.JOHANSSON, A.KALLAS, T.KOTENYOVA, M.MOCHE, M.E.NILSSON, P.NORDLUND, T.NYMAN, C.PERSSON, J.SAGEMARK, L.SVENSSON, A.G.THORSELL, S.VAN DEN BERG, J.WEIGELT

About this structure

The inhibitor of apoptosis (IAP) proteins are important suppressors of apoptosis, as they bind directly to caspases and inhibit their actions. A zinc-binding fold, termed the BIR (baculovirus IAP repeat) domain, present in at least one copy in IAPs, is responsible for this action, although not all BIR domains interact with caspases. BIR domains are involved in protein-protein interactions, most prominently with the caspases and mitochondria-derived IAP antagonists such as Smac/DIABLO and OMI.

Overexpression of IAP proteins in human cancers has been shown to suppress apoptosis induced by a variety of stimuli (1). Peptides based on the processed N-terminus of Smac/DIABLO have been demonstrated to bind to a surface groove of BIR domains of the IAPs ML-IAP and XIAP (2,3), and such peptides can negate the ability of overexpressed IAPs to suppress drug-induced apoptosis (4-5).

The 1.8 Å structure of the second BIR domain of human BIRC1 crystallized as a monomer. The structure contains one Zn ion coordinated by three cysteines and one histidine residue. The crystallized construct includes the BIR1-BIR2 linker sequence and the N-terminal hexa-histidine affinity tag was cleaved off prior to crystallization. The resulting N-terminus is found wrapped around the fold, stabilized by the tight binding of the first four residues in the Smac-binding groove. As much attention is paid to the function of BIR domains, novel structures like this one contribute important information about their different binding specificities.

References

  1. Salvesen, G. S., and Duckett, C. S. (2002) Nat. ReV. 3, 401-10.0
  2. Zobel, K., et al. (2006) ACS Chem Biol. 1(9), 525-33
  3. Franklin, MC et al. (2003) Biochemistry 42, 8223-8231.
  4. Vucic, D., et al.. (2002) J. Biol. Chem. 277, 12275-9.
  5. Fulda, S., et al. (2002) Nat. Med. 8, 808-15.