A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions.

Chittenden, Thomas; Flemington, Cathy; Houghton, Anne B.; Ebb, R. G.; Gallo, Gabriella; Elangovan, B.; Chinnadurai, G.; Lutz, Robert J.

doi:10.1002/j.1460-2075.1995.tb00246.x

Cited by 465 publications

(387 citation statements)

References 33 publications

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“…In BAK, BH3 is sufficient for promoting death as well as dimerization with BCL-X L . 90 BAX homodimerization has been demonstrated to occur by BH3 to BH3 interaction. 91 Deletion of BH3 renders both BAX and BAK non-functional.…”

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confidence: 99%

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t(14;18), a journey to eternity

Meijerink

1997

Leukemia

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The t(14;18) is the most frequent chromosomal aberration observed in follicular non-Hodgkin's lymphoma (NHL), and less frequently in diffuse large cell lymphoma (DLCL). The t(14;18) does not affect overall survival in follicular NHL or DLCL. It provides a unique lymphoma-specific marker that can be used to quantify residual disease during treatment, and may forward evaluation of new treatment protocols. The t(14;18) results in the deregulation of bcl-2, a proto-oncogene that protects against induction of programmed cell death (PCD). Nowadays, a whole family of bcl-2-related genes has been identified and consist of members which can either protect or promote induction of PCD. The family members form protein dimers, and the relative abundance of specific dimers regulates the cellular sensitivity to death signals (the rheostat model). Aberrant expression of different family members in several types of malignancies alter the cellular rheostat and thereby promote cellular resistance to chemotherapy.

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Section: Figurementioning

confidence: 99%

“…91 Deletion of BH3 renders both BAX and BAK non-functional. 90,91 Moreover, a BH3 homologous domain has also been identified in pro-apoptotic molecules BIK/NBK, 92,93 BID 94 and HRK, 95 which are distantly related to the bcl-2 gene family. Therefore, BH3 may encode a new critical death domain.…”

Section: Figurementioning

confidence: 99%

t(14;18), a journey to eternity

Meijerink

1997

Leukemia

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“…A similar control mechanism of BH3 domain-induced oligomerization was proposed for other 'multidomain' BCL-2 family members. 22 The conservation of sequential motifs in the BCL family led to detailed investigations of their interactions, and the identification of the BH3 motif as an interaction site in BAK's binding to BCL-2 and BCL-X L. 23 In elegant structural studies, 24 the Fesik laboratory showed that this was the result of the BH3 forming a helix analogous to its fold in full-length analogs, producing complexes with a BH1 and BH2 face of BCL-X L through hydrophobic and electrostatic contacts. Various screening methods including chemical-shift perturbation/NMR were used to identify small molecule mimics of the BAK BH3 motif 25 that are able to bind to BCL-X L .…”

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NMR determination that an extended BH3 motif of pro-apoptotic BID is specifically bound to BCL-XL

Shekhtman

Ghose

et al. 2006

Magn. Reson. Chem.

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The BH3 motif of the pro-survival family of proteins, BCL, is also present in pro-apoptotic proteins like BID and BAX. Homo-and hetero-oligomerization interactions of the BH3 motif are generally recognized as the critical component of their apoptotic activities. In full-length BID, the putative hydrophobic binding surface of its BH3 motif is substantially occluded by intramolecular contacts, many of which are removed on BID's transformation to tBID by cleavage with caspase 8, required for tBID's pro-apoptotic action on mitochondria, thereby releasing cytochrome c. KeywordsNMR; 1 H; 13 C; 15 N; BID; BCL-X L ; apoptosis; BH3 motif; death agonist; helical propensity As a step toward more complete characterization of the hetero-oligomeric complexes of the BCL interacting domain (BID) and B cell lymphoma associated gene (BCL) family of molecules, we report here the formation of a tight complex of the BH3 motif sequence of BID with BCL-X L . In contrast to the previous report of BAK BH3 motif with BCL-X L , the BID BH3 peptide (PDSESQEEIMHNIARKLAQIGDDI) forms an α-helix significantly extended to the N-terminus, as monitored by 15 N{ 1 H} nOe determination and by 13 C chemical shifts. Modeling of the BID BH3 motif/BCL-X L based on the previous structure showed that the extended helix fitted well into an extended cavity in BCL-X L . Mutagenesis of the peptide and BCL-X L based on this model identified the key residues in the BH3 motif, but suggested that some conformational flexibility is likely in the BCL surface.The extended recognition of BID's BH3 motif indicates that the range of specificity for binding partners to the BCL family is highly complex, that specificity may incorporate conformational changes from the free proteins, and that these may be of significance in the specific targeting of these complexes to membrane and other targets.Programmed cell death is a highly evolutionarily conserved biological process critical for development and homeostasis in multicellular organisms. 1,2 This process allows the removal of redundant or damaged cells, playing a vital role in normal cellular development, tissue homeostasis, and immunological defense. 3,4 Deregulation of this pathway can contribute to † Dedicated in memory of Stanley J. Korsmeyer.

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“…We have identi®ed and cloned four cellular proteins that interact with viral (E1B-19K and EBV-BHRF1) and cellular (BCL-2 and BCL-X L ) BCL-2 family anti-apoptosis proteins (Boyd et al, 1994(Boyd et al, , 1995. These proteins include BIK, the founding member of the`BH3-alone' pro-apoptotic proteins (Boyd et al, 1995;Chittenden et al, 1995;Han et al, 1996), BNIP1, BNIP2 and BNIP3 (Boyd et al, 1994). Among the latter three proteins, BNIP3 has been shown to be a member of the`BH3-alone' proteins (Yasuda et al, 1998a).…”

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confidence: 99%