Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases

Hunkeler, Moritz; Jin, Cyrus Y.; Fischer, Eric S.

doi:10.1126/science.ade5750

Cited by 17 publications

(12 citation statements)

References 85 publications

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“…Additionally, most of these proteins can bind to specific caspases to mediate the antiapoptosis effects . BIRC6 is a member with the largest molecular weight and is the only one known to be linked to the membrane so far . In addition to the BIRC region that is specific to the family, BIRC6 also possesses a ubiquitin-conjugating enzyme E2 (UBC) domain, indicating its involvement in ubiquitin ligase activity .…”

Section: Discussionmentioning

confidence: 99%

BIRC6 Modulates the Protein Stability of Axin to Regulate the Growth, Stemness, and Resistance of Renal Cancer Cells via the β-Catenin Pathway

Zhong,

Wang,

Zhang

et al. 2024

ACS Omega

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The mechanism underlying the development of renal cell carcinoma (RCC) remains unclear, and effective prevention and therapeutic measures are lacking. BIRC6, a protein inhibitor of apoptosis, has attracted great interest. Our data indicated that overexpression of BIRC6 elevated cell growth, colony formation, migration, and invasion of cultured RCC cells, while siRNA knockdown of BIRC6 suppressed these processes. Additionally, BIRC6 was highly expressed in RCC clinical samples along with a downregulated level of Axin. Immunoprecipitation assays found that BIRC6 interacted with Axin and the two proteins colocalized within the cytoplasm of RCC cells. Overexpression of BIRC6 promoted the ubiquitination modification of Axin, while genetic knockdown of BIRC6 suppressed it. Furthermore, overexpression of BIRC6 significantly promoted the turnover of Axin, suggesting BIRC6's inhibitory effect on Axin protein stability. BIRC6 was also upregulated in cancer stem-like cells of RCC and increased the drug resistance of RCC cells against sunitinib. Western blotting assays showed that the overexpression of BIRC6 upregulated CXCR4 protein expression and activated the β-catenin pathway. Two cell lines were then constructed with BIRC6 overexpressed by lentiviruses. Pharmacological administration of a Wnt/β-catenin inhibitor, XAV-939, or genetic knockdown of β-catenin inhibited cell growth, tumor sphere formation, colony formation, migration, and invasion of BIRC6-overexpressed cells. In vivo administration of XAV-939 markedly suppressed the tumorigenesis of BIRC6-overexpressed RCC cells in nude mice. In conclusion, we propose that BIRC6 activates the β-catenin signaling pathway via mediating the ubiquitination and degradation of Axin, promoting the growth, stemness, and drug resistance of RCC cells. This project aims to elucidate the role of BIRC6 as a potential therapeutic target and provide new insights into the clinical treatment of RCC.

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Section: Discussionmentioning

confidence: 99%

BIRC6 Modulates the Protein Stability of Axin to Regulate the Growth, Stemness, and Resistance of Renal Cancer Cells via the β-Catenin Pathway

Zhong,

Wang,

Zhang

et al. 2024

ACS Omega

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“…Nonetheless, the recovery of acceptable solutions for the two cIAP systems comes at the cost of overall performance at the early stages (Top 5 to Top 20, Figure 3E ). It is important to note that, recently, researchers have pointed out to the fact that the cIAP structures used in this work contain only one domain of the full cIAP protein and that the full length cIAP interacts with their substrates from different domains, which bind different parts of the substrate 84 , thus making a proper prediction of these PPIs challenging.…”

Section: Discussionmentioning

confidence: 99%

Rational Prediction of PROTAC-compatible Protein-Protein Interfaces by Molecular Docking

Pereira

Jiménez‐García²,

Pellarin

et al. 2023

Preprint

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Proteolysis targeting chimeras (PROTACS) are ligands that can mediate interaction between a protein target and a E3 ligase, forming a ternary complex bound to the ubiquitination machinery, leading to target degradation. This technology has become an exciting new avenue for therapeutic development, with currently two PROTACS in clinical trials targeting cancer. Nonetheless, several PROTAC drug discovery campaigns still rely on serendipity. Here, we describe a general and efficient protocol which combines restraint-based LightDock, energy-based rescoring and minimal solvent-accessible surface distance filtering to produce PROTAC-compatible PPIs. Benchmarking our protocol using a manually curated dataset of 16 ternary complex crystals, accuracies of 94% and 70% were achieved on the redocking and realistic docking experiments starting from unbound protein structures, respectively, evaluated using the CAPRI standards and DockQ. Our protocol is both accurate and computationally efficient, with potential to accelerate PROTAC drug design campaigns, particularly when the ternary complex or PROTAC are unknown.

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“…(E) Showcase comparing the 6W8I crystal structure (gray) to the best prediction (ranked sixth) obtained using our workflow (colored). It is important to note that, recently, researchers have pointed out to the fact that the cIAP structures used in this work contain only one domain of the full cIAP protein and that the full-length cIAP interacts with their substrates from different domains, which bind different parts of the substrate, 84 thus making a proper prediction of these PPIs challenging. Our protocol is general and applicable to any ligase-target protein pair as it only requires the corresponding ligand-bound structures of the monomeric forms for each protein.…”

Section: ■ Discussionmentioning

confidence: 99%

Rational Prediction of PROTAC-Compatible Protein–Protein Interfaces by Molecular Docking

Pereira,

Jiménez-García,

Pellarin

et al. 2023

J. Chem. Inf. Model.

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Proteolysis targeting chimeras (PROTACs) are heterobifunctional ligands that mediate the interaction between a protein target and an E3 ligase, resulting in a ternary complex, whose interaction with the ubiquitination machinery leads to target degradation. This technology is emerging as an exciting new avenue for therapeutic development, with several PROTACs currently undergoing clinical trials targeting cancer. Here, we describe a general and computationally efficient methodology combining restraint-based docking, energy-based rescoring, and a filter based on the minimal solvent-accessible surface distance to produce PROTAC-compatible PPIs suitable for when there is no a priori known PROTAC ligand. In a benchmark employing a manually curated data set of 13 ternary complex crystals, we achieved an accuracy of 92% when starting from bound structures and 77% when starting from unbound structures, respectively. Our method only requires that the ligand-bound structures of the monomeric forms of the E3 ligase and target proteins be given to run, making it general, accurate, and highly efficient, with the ability to impact early-stage PROTAC-based drug design campaigns where no structural information about the ternary complex structure is available.

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Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases

Cited by 17 publications

References 85 publications

BIRC6 Modulates the Protein Stability of Axin to Regulate the Growth, Stemness, and Resistance of Renal Cancer Cells via the β-Catenin Pathway

BIRC6 Modulates the Protein Stability of Axin to Regulate the Growth, Stemness, and Resistance of Renal Cancer Cells via the β-Catenin Pathway

Rational Prediction of PROTAC-compatible Protein-Protein Interfaces by Molecular Docking

Rational Prediction of PROTAC-Compatible Protein–Protein Interfaces by Molecular Docking

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