Structural Mechanism for Regulation of Bcl-2 protein Noxa by phosphorylation

Karim, Christine B.; Espinoza-Fonseca, L. Michel; James, Zachary M.; Hanse, Eric A.; Gaynes, Jeffrey S.; Thomas, David D.; Kelekar, Ameeta

doi:10.1038/srep14557

Cited by 16 publications

(18 citation statements)

References 22 publications

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“…Due to oxidative stress, the mitochondrial dysfunction by accumulation of intracellular reactive oxygen species (ROS) has been associated with apoptosis. As a well-known anti-apoptotic gene, Bcl-2 stabilizes mitochondria, blocks the classic apoptotic pathways, and suppresses autophagy through binding with Beclin 1 13 14 15 16 17 . In the current study, we found that Bcl-2 was controlled by IGF-1 in UUO, as a major mechanism for the renal epithelial cells to resist the injury and survive.…”

Section: Discussionmentioning

confidence: 99%

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IGF-1 protects tubular epithelial cells during injury via activation of ERK/MAPK signaling pathway

Niu

et al. 2016

Sci Rep

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Injury of renal tubular epithelial cells can induce acute renal failure and obstructive nephropathy. Previous studies have shown that administration of insulin-like growth factor-1 (IGF-1) ameliorates the renal injury in a mouse unilateral ureteral obstruction (UUO) model, whereas the underlying mechanisms are not completely understood. Here, we addressed this question. We found that the administration of IGF-1 significantly reduced the severity of the renal fibrosis in UUO. By analyzing purified renal epithelial cells, we found that IGF-1 significantly reduced the apoptotic cell death of renal epithelial cells, seemingly through upregulation of anti-apoptotic protein Bcl-2, at protein but not mRNA level. Bioinformatics analyses and luciferase-reporter assay showed that miR-429 targeted the 3′-UTR of Bcl-2 mRNA to inhibit its protein translation in renal epithelial cells. Moreover, IGF-1 suppressed miR-429 to increase Bcl-2 in renal epithelial cells to improve survival after UUO. Furthermore, inhibition of ERK/MAPK signaling pathway in renal epithelial cells abolished the suppressive effects of IGF-1 on miR-429 activation, and then the enhanced effects on Bcl-2 in UUO. Thus, our data suggest that IGF-1 may protect renal tubular epithelial cells via activation of ERK/MAPK signaling pathway during renal injury.

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Section: Discussionmentioning

confidence: 99%

“…Bid, Bak, Bad, and apoptosis suppressors, e.g. B-cell lymphoma 2 (Bcl-2)1314151617. Bcl-2 is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inducing (pro-apoptotic) or inhibiting (anti-apoptotic) apoptosis1314151617.…”

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confidence: 99%

IGF-1 protects tubular epithelial cells during injury via activation of ERK/MAPK signaling pathway

Niu

et al. 2016

Sci Rep

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“…In this study, we have used solid-phase peptide synthesis (SPPS), circular dichroism (CD), and EPR to detect the structural dynamics of RyRp, bound to apoCaM and bound to Ca 2þ -CaM in solution. EPR is a powerful technique for investigating structural changes in proteins and protein/enzyme complexes in response to regulatory modifications (19)(20)(21). In these studies, peptides are typically prepared by 9-fluorenylmethoxycarbonyl SPPS (22), which permits the incorporation of nonnatural amino acids into the peptide sequence, including the spin-labeled amino acid 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid (TOAC).…”

Section: Introductionmentioning

confidence: 99%

Calcium-Dependent Structural Dynamics of a Spin-Labeled RyR Peptide Bound to Calmodulin

Her

McCaffrey

Thomas

et al. 2016

Biophysical Journal

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We have used chemical synthesis, electron paramagnetic resonance (EPR), and circular dichroism to detect and analyze the structural dynamics of a ryanodine receptor (RyR) peptide bound to calmodulin (CaM). The skeletal muscle calcium release channel RyR1 is activated by Ca 2þ -free CaM and inhibited by Ca 2þ -bound CaM. To probe the structural mechanism for this regulation, wild-type RyRp and four spin-labeled derivatives were synthesized, each containing the nitroxide probe 2,2,6,6-tetramethyl-piperidine-1-oxyl-4-amino-4-carboxylic acid substituted for a single amino acid. In 2,2,6,6-tetramethyl-piperidine-1-oxyl-4-amino-4-carboxylic acid, the probe is rigidly and stereospecifically coupled to the a-carbon, enabling direct detection by EPR of peptide backbone structural dynamics. In the absence of CaM, circular dichroism indicates a complete lack of secondary structure, while 40% trifluoroethanol (TFE) induces >90% helicity and is unperturbed by the spin label. The EPR spectrum of each spin-labeled peptide indicates nanosecond dynamic disorder that is substantially reduced by TFE, but a significant gradient in dynamics is observed, decreasing from N-to C-terminus, both in the presence and absence of TFE. When bound to CaM, the probe nearest RyRp's N-terminus shows rapid rotational motion consistent with peptide backbone dynamics of a locally unfolded peptide, while the other three sites show substantial restriction of dynamics, consistent with helical folding. The two N-terminal sites, which bind to the C-lobe of CaM, do not show a significant Ca 2þ -dependence in mobility, while both C-terminal sites, which bind to the N-lobe of CaM, are significantly less mobile in the presence of bound Ca 2þ . These results support a model in which the interaction of RyR with CaM is nonuniform along the peptide, and the primary effect of Ca 2þ is to increase the interaction of the C-terminal portion of the peptide with the N-terminal lobe of CaM. These results provide, to our knowledge, new insight into the Ca 2þ -dependent regulation of RyR by CaM.

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“…39 As a final recent example, simulations have detected a claw-like structure in the long-time dynamics of a small, apoptosis-related intrinsically disordered protein (IDP) known as Noxa. 40 Include Figure 2 here.…”

Section: Introductionmentioning

confidence: 99%

Claws, Disorder, and Conformational Dynamics of the C-Terminal Region of Human Desmoplakin

McAnany

Mura

2016

J. Phys. Chem. B

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Multicellular organisms consist of cells that interact via elaborate adhesion complexes. Desmosomes are membrane-associated adhesion complexes that mechanically tether the cytoskeletal intermediate filaments (IFs) between two adjacent cells, creating a network of tough connections in tissues such as skin and heart. Desmoplakin (DP) is the key desmosomal protein that binds IFs, and the DP • IF association poses a quandary: desmoplakin must stably and tightly bind IFs to maintain the structural integrity of the desmosome. Yet, newly synthesized DP must traffick along the cytoskeleton to the site of nascent desmosome assembly without 'sticking' to the IF network, implying weak or transient DP···IF contacts. Recent work reveals that these contacts are modulated by post-translational modifications (PTMs) in DP's C-terminal tail. Using molecular dynamics simulations, we have elucidated the structural basis of these PTM-induced effects. Our simulations, nearing 2 µs in aggregate, indicate that phosphorylation of S2849 induces an 'arginine claw' in desmoplakin's C-terminal tail (DP CTT ). If a key arginine, R2834, is methylated, the DP CTT preferentially samples conformations that are geometrically well-suited as substrates for processive phosphorylation by the cognate kinase GSK3. We suggest that DP CTT is a molecular switch that modulates, via its conformational dynamics, DP's efficacy as a substrate for GSK3.Finally, we show that the fluctuating DP CTT can contact other parts of DP, suggesting a competitive binding mechanism for the modulation of DP···IF interactions.2

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Structural Mechanism for Regulation of Bcl-2 protein Noxa by phosphorylation

Cited by 16 publications

References 22 publications

IGF-1 protects tubular epithelial cells during injury via activation of ERK/MAPK signaling pathway

IGF-1 protects tubular epithelial cells during injury via activation of ERK/MAPK signaling pathway

Calcium-Dependent Structural Dynamics of a Spin-Labeled RyR Peptide Bound to Calmodulin

Claws, Disorder, and Conformational Dynamics of the C-Terminal Region of Human Desmoplakin

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