Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity-1

RP2chimeras and the ΔD4 IRP1 deletion mutant; the IRP1 constructs are tagged with FLAG and the others with HA epitopes. (B-E) H1299 cells engineered to express wild type IRP1, ΔD4 IRP1, wild type IRP2 or the above chimeras (in three independent clones) were treated overnight (14 h) with 30 μg/ml FAC or 100 μM hemin, and lysates were subjected to Western blotting with FLAG or HA (top) and β-actin (bottom) antibodies.<p><b>Copyright information:</b></p><p>Taken from "Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity"</p><p>http://www.biomedcentral.com/1471-2199/9/15</p><p>BMC Molecular Biology 2008;9():15-15.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2267205.</p><p></p

Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity-3

+) or without (-) tetracycline. (A and C) Cytoplasmic extracts were analyzed for IRE-binding activity with a P-labeled IRE probe in the absence or presence of 0.2 μg purified polyclonal HA antibody. The positions of the IRE/IRP complexes, the HA-supershifts and excess free IRE probe are indicated by arrows. (B) Analysis of TfR1 expression in two clones expressing IRP1-IRP2. Lysates were subjected to Western blotting with HA (top), TfR1 (middle) and β-actin (bottom) antibodies.<p><b>Copyright information:</b></p><p>Taken from "Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity"</p><p>http://www.biomedcentral.com/1471-2199/9/15</p><p>BMC Molecular Biology 2008;9():15-15.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2267205.</p><p></p

Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity-5

Ides of IRP2 (grey) at their C-termini. (B and C) H1299 cells engineered to express these constructs (in two independent clones) were treated overnight (14 h) with the indicated concentrations of FAC and lysates were subjected to Western blotting with luciferase (top) and β-actin (bottom) antibodies.<p><b>Copyright information:</b></p><p>Taken from "Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity"</p><p>http://www.biomedcentral.com/1471-2199/9/15</p><p>BMC Molecular Biology 2008;9():15-15.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2267205.</p><p></p

Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity-0

Ks domains 3 and 4, and the C-terminal HA tag. The 73 amino acids sequence (73d) within domain 1 is highlighted in gray. (B-G) H1299 cells engineered to express wild type IRP2 or two independent clones of the above mutants (except ΔD1) were treated overnight (14 h) with 100 μM hemin or 30 μg/ml FAC and lysates were subjected to Western blotting with HA (top) and β-actin (bottom) antibodies. No clones expressing ΔD1 could be isolated.<p><b>Copyright information:</b></p><p>Taken from "Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity"</p><p>http://www.biomedcentral.com/1471-2199/9/15</p><p>BMC Molecular Biology 2008;9():15-15.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2267205.</p><p></p

Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity-2

E metabolically labeled for 2 h with S-methionine/cysteine. Subsequently, the cells were chased for the indicated time intervals in cold media in the absence or presence of 30 μg/ml FAC. Cytoplasmic lysates (500 μg) were subjected to quantitative immunoprecipitation with 1 μg HA (Santa Cruz) or FLAG (Sigma) antibodies. Immunoprecipitated proteins were analyzed by SDS-PAGE on a 7.5% gel and visualized by autoradiography. The radioactive bands were quantified by phosphorimaging. The percentage of residual radioactivity from three independent experiments (mean ± SD) is plotted against time.<p><b>Copyright information:</b></p><p>Taken from "Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity"</p><p>http://www.biomedcentral.com/1471-2199/9/15</p><p>BMC Molecular Biology 2008;9():15-15.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2267205.</p><p></p

Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity-4

Ks domains 3 and 4, and the C-terminal HA tag. (B-F) H1299 cells engineered to express the above mutants (in two or three independent clones) were treated overnight (14 h) with 30 μg/ml FAC and lysates were subjected to Western blotting with HA (top) and β-actin (bottom) antibodies. The different migration of wild type IRP2 and the ΔC60 and ΔC168 deletion mutants is illustrated in (B).<p><b>Copyright information:</b></p><p>Taken from "Iron-dependent degradation of IRP2 requires its C-terminal region and IRP structural integrity"</p><p>http://www.biomedcentral.com/1471-2199/9/15</p><p>BMC Molecular Biology 2008;9():15-15.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2267205.</p><p></p

Discovery of a Novel, Potent Spirocyclic Series of γ‑Secretase Inhibitors

In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer’s disease (AD), demonstrating reduction of amyloid-β (Aβ) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate <b>18a­(−)</b> features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs

Magnetization and spin gap in two-dimensional organic ferrimagnet BIPNNBNO

A magnetization process in the two-dimensional ferrimagnet BIPNNBNO is analyzed. The compound consists of ferrimagnetic (1,1/2) chains coupled by two sorts of antiferromagnetic interaction. Whereas the behavior of the magnetization curve in higher magnetic fields can be understood within a process for the separate ferrimagnetic chain, the appearance of the singlet plateau at lower fields is an example of non-Lieb-Mattis type ferrimagnetism. By using the exact diagonalization technique for finite clusters of size 4×6, 4×8 and 4×10 we show that the interchain frustration coupling plays an essential role in stabilization of the singlet phase. These results are complemented by an analysis of four cylindrically coupled ferrimagnetic (1,1/2) chains via an Abelian bosonization technique and an effective theory based on the XXZ spin-1/2 Heisenberg model when the interchain interactions are sufficiently weak/strong, respectively. © 2012 IOP Publishing Ltd