Role of single disulfide linkages in the folding and activity of scyllatoxin-based BH3 domain mimetics

2017 ◽  
Vol 23 (5) ◽  
pp. 367-373 ◽  
Author(s):  
Danushka Arachchige ◽  
M. Margaret Harris ◽  
Zachary Coon ◽  
Jacob Carlsen ◽  
Justin M. Holub
Keyword(s):  
Bh3 Domain ◽  
Disulfide Linkages

Role of disulfide linkages in tachyplesin-lipid interactions

Biochemistry ◽  
1993 ◽  
Vol 32 (43) ◽  
pp. 11704-11710 ◽  
Author(s):  
Katsumi Matsuzaki ◽  
Mitsuya Nakayama ◽  
Masaru Fukui ◽  
Akira Otaka ◽  
Susumu Funakoshi ◽  
...  
Keyword(s):  
Lipid Interactions ◽  
Disulfide Linkages

scholarly journals The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins

2009 ◽  
Vol 186 (3) ◽  
pp. 355-362 ◽  
Author(s):  
Delphine Mérino ◽  
Maybelline Giam ◽  
Peter D. Hughes ◽  
Owen M. Siggs ◽  
Klaus Heger ◽  
...  
Keyword(s):  
Family Members ◽  
Binding Specificity ◽  
In Vitro Studies ◽  
Genetic Approach ◽  
Activation Model ◽  
Bh3 Domain ◽  
Indirect Activation

Proteins of the Bcl-2 family are critical regulators of apoptosis, but how its BH3-only members activate the essential effectors Bax and Bak remains controversial. The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly. As numerous in vitro studies have not resolved this issue, we have investigated Bim's activity in vivo by a genetic approach. Because the BH3 domain determines binding specificity for Bcl-2 relatives, we generated mice having the Bim BH3 domain replaced by that of Bad, Noxa, or Puma. The mutants bound the expected subsets of prosurvival relatives but lost interaction with Bax. Analysis of the mice showed that Bim's proapoptotic activity is not solely caused by its ability to engage its prosurvival relatives or solely to its binding to Bax. Thus, initiation of apoptosis in vivo appears to require features of both models.

Death by association: BH3 domain-only proteins and liver injury

2005 ◽  
Vol 289 (6) ◽  
pp. G987-G990 ◽  
Author(s):  
E. S. Baskin-Bey ◽  
G. J. Gores
Keyword(s):  
Cell Death ◽  
Liver Injury ◽  
Mitochondrial Dysfunction ◽  
Liver Cell ◽  
Liver Diseases ◽  
Chronic Liver Diseases ◽  
Concise Review ◽  
Bh3 Domain ◽  
A Cell

Apoptosis, a prominent form of cell death, is a prime feature of many acute and chronic liver diseases. Apoptosis requires mitochondrial dysfunction, which is regulated by proteins of the Bcl-2 family. Whether or not a cell should live or die is controlled by the interaction of multidomain Bcl-2 proteins with proapoptotic BH3 domain-only proteins of this family. Current models suggest multidomain, antiapoptotic Bcl-2 proteins prevent mitochondrial dysfunction by sequestering and/or preventing activation of its proapoptotic relatives. BH3-only proteins initiate cell death by neutralizing and or ligating multidomain prosurvival Bcl-2 proteins. Thus BH3 domain-only proteins are paramount in the apoptotic process as exemplified by the role of the BH3 domain-only protein Bid in liver injury. In this concise review, we will focus on how these BH3 domain-only proteins are regulated in the cell, their association with the Bcl-2 family of proteins, and finally, current information regarding their involvement in liver cell apoptosis and injury.

scholarly journals The chaperone Hsp70 is a BH3 receptor activated by the pro-apoptotic Bim to stabilize anti-apoptotic clients

2020 ◽  
Vol 295 (37) ◽  
pp. 12900-12909
Author(s):  
Zongwei Guo ◽  
Ting Song ◽  
Ziqian Wang ◽  
Donghai Lin ◽  
Keke Cao ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Cell Fate ◽  
Protein Misfolding ◽  
Structural Basis ◽  
Titration Calorimetry ◽  
Allosteric Site ◽  
Transverse Relaxation ◽  
Bh3 Domain

The chaperone heat shock protein 70 (Hsp70) is crucial for avoiding protein misfolding under stress, but is also up-regulated in many kinds of cancers, where its ability to buffer cellular stress prevents apoptosis. Previous research has suggested Hsp70 interacts with pro-apoptotic Bcl-2 family proteins, including Bim and Bax. However, a definitive demonstration of this interaction awaits, and insights into the structural basis and molecular mechanism remain unclear. Earlier studies have identified a Bcl-2 homology 3 (BH3) domain present in Bcl-2 family members that engages receptors to stimulate apoptosis. We now show that Hsp70 physically interacts with pro-apoptotic multidomain and BH3-only proteins via a BH3 domain, thereby serving as a novel BH3 receptor, using in vitro fluorescent polarization (FP), isothermal titration calorimetry (ITC), and cell-based co-immunoprecipitation (co-IP) experiments, 1H-15N-transverse relaxation optimized spectroscopy (TROSY-HSQC), trypsin proteolysis, ATPase activity, and denatured rhodanese aggregation measurements further demonstrated that BimBH3 binds to a novel allosteric site in the nucleotide-binding domain (NBD) of Hsp70, by which Bim acts as a positive co-chaperone to promote the ATPase activity and chaperone functions. A dual role of Hsp70's anti-apoptotic function was revealed that when it keeps Bim in check to inhibit apoptosis, it simultaneously stabilizes oncogenic clients including AKT and Raf-1 with the aid of Bim. Two faces of Bim in cell fate regulation were revealed that in opposite to its well-established pro-apoptotic activator role, Bim could help the folding of oncogenic proteins.

The Role of Disulfide Linkages in Desulfurization Chemistry: The Reactions of Benzenethiol on a Sulfur-Covered Mo(110) Surface

1994 ◽  
Vol 116 (18) ◽  
pp. 8328-8334 ◽  
Author(s):  
M. K. Weldon ◽  
M. E. Napier ◽  
Benjamin C. Wiegand ◽  
C. M. Friend ◽  
P. Uvdal
Keyword(s):  
Disulfide Linkages

Bcl-2-family proteins: the role of the BH3 domain in apoptosis

1998 ◽  
Vol 8 (8) ◽  
pp. 324-330 ◽  
Author(s):  
Ameeta Kelekar ◽  
Craig B Thompson
Keyword(s):  
Bh3 Domain

scholarly journals Bcl-XL specifically activates Bak to induce swelling and restructuring of the endoplasmic reticulum

2005 ◽  
Vol 168 (5) ◽  
pp. 723-734 ◽  
Author(s):  
Martina Klee ◽  
Felipe X. Pimentel-Muiños
Keyword(s):  
Endoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Functional Divergence ◽  
Deficient Mouse ◽  
Channel Activity ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Bh3 Domain ◽  
Additional Capacity

Bcl-2 family members Bak and Bax constitute a mitochondrial gateway for multiple death pathways. Both proteins are also present in the endoplasmic reticulum where they control apoptosis through the regulation of calcium levels. We show here that reticular Bak has the additional capacity of modulating the structure of this organelle. Coexpression of Bak and Bcl-XL provokes extensive swelling and vacuolization of reticular cisternae. A Bak version lacking the BH3 domain suffices to induce this phenotype, and reticular targeting of this mutant retains the activity. Expression of upstream BH3-only activators in similar conditions recapitulates ER swelling and vacuolization if ryanodine receptor calcium channel activity is inhibited. Experiments with Bak and Bax-deficient mouse embryonic fibroblasts show that endogenous Bak mediates the effect, whereas Bax is mainly irrelevant. These results reveal a previously unidentified role of Bak in regulating reticular conformation. Because this activity is absent in Bax, it constitutes one of the first examples of functional divergence between the two multidomain homologues.

scholarly journals Ligand-Independent Antiapoptotic Function of Estrogen Receptor-β in Lung Cancer Cells

2010 ◽  
Vol 24 (9) ◽  
pp. 1737-1747 ◽  
Author(s):  
GuangFeng Zhang ◽  
Naveena Yanamala ◽  
Kira L. Lathrop ◽  
Lin Zhang ◽  
Judith Klein-Seetharaman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Estrogen Receptor ◽  
Cell Types ◽  
Mitochondrial Fraction ◽  
Apoptotic Pathway ◽  
Independent Manner ◽  
Bh3 Domain ◽  
Exact Function ◽  
Apoptosis Inducing Agents

Abstract Recent studies have demonstrated the presence of estrogen receptor (ER)β in the mitochondria in various cell types and tissues, but the exact function of this localization remains unclear. In this study, we have examined the function of mitochondrial ERβ in non-small-cell lung cancer (NSCLC) cells. Down-regulation of ERβ by short hairpin RNA constructs sensitized NSCLC cells to various apoptosis-inducing agents such as cisplatin, taxol, and etoposide. The increased growth inhibition and induction of apoptosis in ERβ-knockdown cells was observed irrespective of estrogen treatment, suggesting a ligand-independent role of ERβ in regulating the intrinsic apoptotic pathway. Further, ERβ from the mitochondrial fraction physically interacted with the proapoptotic protein Bad, in a ligand-independent manner. Glutathione-S-transferase pull-down assays and molecular modeling studies revealed that the DNA-binding domain and hinge region of ERβ, and the BH3 domain of Bad were involved in these interactions. Further investigations revealed that ERβ inhibited Bad function by disrupting Bad-Bcl-XL and Bad-Bcl-2 interactions. Reintroduction of ERβ in the mitochondria of ERβ knockdown cells reversed their sensitivity to cisplatin. Overall, our results demonstrate a ligand-independent role of ERβ in regulating apoptosis, revealing a novel function for ERβ in the mitochondria.

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