Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets

Hinds, Mark G.; Smits, C.; Fredericks-Short, R; Risk, Joanna M.; Bailey, Michael F.; Huang, David C.S.; Day, Catherine L.

doi:10.1038/sj.cdd.4401934

Cited by 203 publications

(182 citation statements)

References 44 publications

(110 reference statements)

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“…43 Other members of the BCL-2 family, BH3-only proteins (such as BIM, BAD, and BMF) that serve as key initiators of PCD are largely disordered in solution. 44 Interaction of the disordered BIM, BAD, BMF, BAK, and tBID with several pro-survival BCL-2 family members leads to the formation of an a-helical segment that anchors these BH3-only proteins to the hydrophobic groove of their binding partners. [45][46] In addition to BH3-only proteins shown in Figure 1, pro-survival BCL-2 family members include MCL-1, BFl-1, and BCB-B, all of which are expected to contain long functional IDPRs.…”

Section: Discussionmentioning

confidence: 99%

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

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It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

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“…This is the first demonstration that a BCL-2 family member can be degraded by 26S proteasomes in an Ub-independent manner, and raises the possibility that other BH3-only proteins containing unstructured regions may be degraded in a similar manner in vivo, 29 In more general terms, there is an expanding list of unstructured proteins including p53, p73a, p21 Cip1 IkB, MCL-1 and BIM that are proposed 20S proteasome substrates based on in vitro studies. 12,14,15,22 Our studies with NOXA suggest that some of these proteins may be bona fide 26S proteasome substrates in vivo.…”

Section: Discussionmentioning

confidence: 99%

NOXA, a sensor of proteasome integrity, is degraded by 26S proteasomes by an ubiquitin-independent pathway that is blocked by MCL-1

et al. 2012

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Ubiquitin (Ub)-mediated proteasome-dependent proteolysis is critical in regulating multiple biological processes including apoptosis. We show that the unstructured BH3-only protein, NOXA, is degraded by an Ub-independent mechanism requiring 19S regulatory particle (RP) subunits of the 26S proteasome, highlighting the possibility that other unstructured proteins reported to be degraded by 20S proteasomes in vitro may be bona fide 26S proteasome substrates in vivo. A lysine-less NOXA (NOXA-LL) mutant, which is not ubiquitinated, is degraded at a similar rate to wild-type NOXA. Myeloid cell leukemia 1, but not other antiapoptotic BCL-2 family proteins, stabilizes NOXA by interaction with the NOXA BH3 domain. Depletion of 19S RP subunits, but not alternate proteasome activator REG subunits, increases NOXA half-life in vivo. A NOXA-LL mutant, which is not ubiquitinated, also requires an intact 26S proteasome for degradation. Depletion of the 19S non-ATPase subunit, PSMD1 induces NOXA-dependent apoptosis. Thus, disruption of 26S proteasome function by various mechanisms triggers the rapid accumulation of NOXA and subsequent cell death strongly implicating NOXA as a sensor of 26S proteasome integrity.

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“…19,26,27 These proteins are unstructured in isolation but assume an α-helical fold when bound to BCL-2 pro-survival family members. 28 The exception to this rule is BID, which is produced as an inactive globular protein that is converted into its active form, tBID (truncated BID), through caspase-8-mediated cleavage. 29,30 The BH3-only proteins are able to bind members of the BCL-2-like pro-survival subfamily and some of them can also bind to BAX and BAK, but there are substantial differences in their selectivity of interaction.…”

Section: The Bcl-2-regulated Apoptotic Pathwaymentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

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Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets

Cited by 203 publications

References 44 publications

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

NOXA, a sensor of proteasome integrity, is degraded by 26S proteasomes by an ubiquitin-independent pathway that is blocked by MCL-1

The BCL-2 protein family, BH3-mimetics and cancer therapy

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