Structural Study of the RIPoptosome Core Reveals a Helical Assembly for Kinase Recruitment

Jang, Tae Ho; Zheng, Chao; Li, Jixi; Richards, Claire; Hsiao, Yu-Sheng; Walz, Thomas; Wu, Hao; Park, Hyun Ho

doi:10.1021/bi500585u

Cited by 28 publications

(22 citation statements)

References 33 publications

(83 reference statements)

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“…The extrinsic apoptotic pathway is regulated by the tumor necrosis factor (TNF) family, including FasL (CD9) and TNF‐α, which interact with the TNF‐receptor (TNF‐R) family molecules FAS (CD95), TNF‐R1, and TNF‐R2, respectively ,. Fas‐associated protein with death domain (FADD), an adaptor protein that bridges death receptor signaling and the caspase cascade, is indispensable for the induction of extrinsic apoptotic cell death . After treating MCF‐7 cells with certain concentrations of H‐RuBmp for 12 h, we found that H‐RuBmp dose‐dependently upregulated the expression of death receptor TNF‐R2, triggered apoptosis by recruiting FADD, and activated caspase‐8, caspase‐10 and tBid, the last of which links activation of the death receptor‐dependent and mitochondrial apoptotic pathways (Figure E).…”

Section: Resultsmentioning

confidence: 99%

Aquation Is a Crucial Activation Step for Anticancer Action of Ruthenium(II) Polypyridyl Complexes to Trigger Cancer Cell Apoptosis

Lai

Zhao

et al. 2015

Chemistry An Asian Journal

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Aquation has been proposed as crucial chemical action step for ruthenium (Ru) complexes, but its effects on the action mechanisms remain elusive. Herein, we have demonstrated the aquation process of a potent Ru polypyridyl complex (RuBmp=[Ru(II) (bmbp)(phen)Cl]ClO4 , bmbp=2,6-bis(6-methylbenzimidazol-2-yl) pyridine, phen=phenanthroline) with a chloride ligand, and revealed that aquation of RuBmp effectively enhanced its hydrophilicity and cellular uptake, thus significantly increasing its anticancer efficacy. The aquation products (H-RuBmp=[Ru(II) (bmbp)(phen)Cl]ClO4 , [Ru(II) (bmbp)(phen)(H2 O)]ClO4 , bmbp) exhibited a much higher apoptosis-inducing ability than the intact complex, with involvement of caspase activation, mitochondria dysfunction, and interaction with cell membrane death receptors. H-RuBmp demonstrated a higher interaction potency with the cell membrane and induced higher levels of ROS overproduction in cancer cells to regulate the AKT, MAPK, and p53 signaling pathways. Taken together, this study could provide useful information for fine-tuning the rational design of next-generation metal medicines.

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Section: Resultsmentioning

confidence: 99%

Aquation Is a Crucial Activation Step for Anticancer Action of Ruthenium(II) Polypyridyl Complexes to Trigger Cancer Cell Apoptosis

Lai

Zhao

et al. 2015

Chemistry An Asian Journal

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“…If RIPK3 acts as a kinase or may also modulate the stoichiometry of protein complexes by a presumed scaffold function is an intriguing question that needs to be addressed in the future. 24 , 61 …”

Section: Discussionmentioning

confidence: 99%

Absence of RIPK3 predicts necroptosis resistance in malignant melanoma

et al. 2015

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Acquired or intrinsic resistance to apoptotic and necroptotic stimuli is considered a major hindrance of therapeutic success in malignant melanoma. Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptotic and necroptotic cell death mediated by numerous cell death signalling platforms. In this report we investigated the impact of IAPs for cell death regulation in malignant melanoma. Suppression of IAPs strongly sensitized a panel of melanoma cells to death ligand-induced cell death, which, surprisingly, was largely mediated by apoptosis, as it was completely rescued by addition of caspase inhibitors. Interestingly, the absence of necroptosis signalling correlated with a lack of receptor-interacting protein kinase-3 (RIPK3) mRNA and protein expression in all cell lines, whereas primary melanocytes and cultured nevus cells strongly expressed RIPK3. Reconstitution of RIPK3, but not a RIPK3-kinase dead mutant in a set of melanoma cell lines overcame CD95L/IAP antagonist-induced necroptosis resistance independent of autocrine tumour necrosis factor secretion. Using specific inhibitors, functional studies revealed that RIPK3-mediated mixed-lineage kinase domain-like protein (MLKL) phosphorylation and necroptosis induction critically required receptor-interacting protein kinase-1 signalling. Furthermore, the inhibitor of mutant BRAF Dabrafenib, but not Vemurafenib, inhibited necroptosis in melanoma cells whenever RIPK3 is present. Our data suggest that loss of RIPK3 in melanoma and selective inhibition of the RIPK3/MLKL axis by BRAF inhibitor Dabrafenib, but not Vemurafenib, is critical to protect from necroptosis. Strategies that allow RIPK3 expression may allow unmasking the necroptotic signalling machinery in melanoma and points to reactivation of this pathway as a treatment option for metastatic melanoma.

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“…These clusters should rely on both DD/DD and DED/DED interactions among the DISC component proteins. Structural and biochemical studies on Fas/FADD and RIP1/FADD DD complexes have implicated helical assembly in DD/DD oligomerization (Esposito et al, 2010; Jang et al, 2014; Wang et al, 2010). However, despite structures of isolated DEDs, how DEDs oligomerize and interact with each other remained elusive due to lack of oligomeric structures (Bagneris et al, 2008; Eberstadt et al, 1998; Shen et al, 2015; Yang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex

et al. 2016

Molecular Cell

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Summary Caspase-8 activation can be triggered by death receptor-mediated formation of the death-inducing signaling complex (DISC) and by the inflammasome adaptor ASC. Caspase-8 assembles with FADD at the DISC and with ASC at the inflammasome through its tandem death effector domain (tDED), which is regulated by the tDED-containing cellular inhibitor cFLIP and the viral inhibitor MC159. Here we present the caspase-8 tDED filament structure determined by cryo-electron microscopy. Extensive assembly interfaces not predicted by the previously proposed linear DED chain model were uncovered, and further confirmed by structure-based mutagenesis in filament formation in vitro, and Fas-induced apoptosis and ASC-mediated caspase-8 recruitment in cells. Structurally, the two DEDs in caspase-8 use quasi-equivalent contacts to enable assembly. Using the tDED filament structure as a template, structural analyses reveal the interaction surfaces between FADD and caspase-8, and the distinct mechanisms of regulation by cFLIP and MC159 through comingling and capping, respectively.

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Structural Study of the RIPoptosome Core Reveals a Helical Assembly for Kinase Recruitment

Cited by 28 publications

References 33 publications

Aquation Is a Crucial Activation Step for Anticancer Action of Ruthenium(II) Polypyridyl Complexes to Trigger Cancer Cell Apoptosis

Aquation Is a Crucial Activation Step for Anticancer Action of Ruthenium(II) Polypyridyl Complexes to Trigger Cancer Cell Apoptosis

Absence of RIPK3 predicts necroptosis resistance in malignant melanoma

Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex

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