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Carles Solsona Thomas B. Kahn Carmen L. Badilla Cristina álvarez-Zaldiernas Juan Blasi Julio M. Fernandez Jorge Alegre-Cebollada 《The Journal of biological chemistry》2014,289(39):26722-26732
Neurodegenerative diseases share a common characteristic, the presence of intracellular or extracellular deposits of protein aggregates in nervous tissues. Amyotrophic Lateral Sclerosis (ALS) is a severe and fatal neurodegenerative disorder, which affects preferentially motoneurons. Changes in the redox state of superoxide dismutase 1 (SOD1) are associated with the onset and development of familial forms of ALS. In human SOD1 (hSOD1), a conserved disulfide bond and two free cysteine residues can engage in anomalous thiol/disulfide exchange resulting in non-native disulfides, a hallmark of ALS that is related to protein misfolding and aggregation. Because of the many competing reaction pathways, traditional bulk techniques fall short at quantifying individual thiol/disulfide exchange reactions. Here, we adapt recently developed single-bond chemistry techniques to study individual disulfide isomerization reactions in hSOD1. Mechanical unfolding of hSOD1 leads to the formation of a polypeptide loop held by the disulfide. This loop behaves as a molecular jump rope that brings reactive Cys-111 close to the disulfide. Using force-clamp spectroscopy, we monitor nucleophilic attack of Cys-111 at either sulfur of the disulfide and determine the selectivity of the reaction. Disease-causing mutations G93A and A4V show greatly altered reactivity patterns, which may contribute to the progression of familial ALS. 相似文献
3.
M Kahn H Sugawara P McGowan K Okuno S Nagoya K E Hellstr?m I Hellstr?m P Greenberg 《Journal of immunology (Baltimore, Md. : 1950)》1991,146(9):3235-3241
p97 is a human tumor-associated Ag present on most melanoma cells that represents a possible target for immunologic attack. To evaluate the capacity of T cells reactive with this protein to promote elimination of melanoma cells expressing p97, a murine model was developed by transfecting a C3H/HeN melanoma with the p97 cDNA, generating p97-specific CD4+ T cells by in vivo immunization of C3H/HeN mice with a vaccinia/p97 recombinant virus followed by in vitro cloning with soluble p97 protein, and determining whether these CD4+ T cells could mediate rejection of pulmonary metastases. Characterization of the T cell clones demonstrated the presence of both I-Ak and I-Ek-restricted clones, although the majority of clones recognized p97 in the context of I-Ek. Analysis of clonal specificity using truncated p97 proteins revealed that at least three epitopes were immunogenic, and further studies with overlapping 15-amino acid peptides from a region of the p97 molecule defined by these truncated proteins identified an immunodominant epitope responsible for the majority of the I-Ek response. The T cell clones were not capable of directly recognizing the p97-expressing melanoma cells but responded to the tumor if syngeneic APC were present to process the tumor-derived p97 Ag. The therapeutic efficacy of these CD4+ T cell clones was evaluated in an adoptive therapy model in which mice bearing metastatic pulmonary lesions were treated by i.v. administration of the p97-specific cells. Despite the inability of the CD4+ clones to directly respond to or lyse the tumor cells, the clones were effective in promoting tumor eradication. In vitro studies demonstrated that this may have reflected secretion of lymphokines that activated macrophages to lyse the tumor. The results suggest that noncytolytic p97-specific CD4+ T cell clones can be effective in therapy of pulmonary melanoma metastases. Moreover, if human T cells reactive with the p97 protein could be generated, the expression of this tumor-associated Ag in melanoma cells might be adequate for such T cells to mediate a therapeutic antitumor response. 相似文献
4.
Daniel T. Meier Ling-Hsien Tu Sakeneh Zraika Meghan F. Hogan Andrew T. Templin Rebecca L. Hull Daniel P. Raleigh Steven E. Kahn 《The Journal of biological chemistry》2015,290(51):30475-30485
Deposition of human islet amyloid polypeptide (hIAPP, also known as amylin) as islet amyloid is a characteristic feature of the pancreas in type 2 diabetes, contributing to increased β-cell apoptosis and reduced β-cell mass. Matrix metalloproteinase-9 (MMP-9) is active in islets and cleaves hIAPP. We investigated whether hIAPP fragments arising from MMP-9 cleavage retain the potential to aggregate and cause toxicity, and whether overexpressing MMP-9 in amyloid-prone islets reduces amyloid burden and the resulting β-cell toxicity. Synthetic hIAPP was incubated with MMP-9 and the major hIAPP fragments observed by MS comprised residues 1–15, 1–25, 16–37, 16–25, and 26–37. The fragments 1–15, 1–25, and 26–37 did not form amyloid fibrils in vitro and they were not cytotoxic when incubated with β cells. Mixtures of these fragments with full-length hIAPP did not modulate the kinetics of fibril formation by full-length hIAPP. In contrast, the 16–37 fragment formed fibrils more rapidly than full-length hIAPP but was less cytotoxic. Co-incubation of MMP-9 and fragment 16–37 ablated amyloidogenicity, suggesting that MMP-9 cleaves hIAPP 16–37 into non-amyloidogenic fragments. Consistent with MMP-9 cleavage resulting in largely non-amyloidogenic degradation products, adenoviral overexpression of MMP-9 in amyloid-prone islets reduced amyloid deposition and β-cell apoptosis. These findings suggest that increasing islet MMP-9 activity might be a strategy to limit β-cell loss in type 2 diabetes. 相似文献
5.
Nicholas C. Davy Marius Koch Guy Olivier Ngongang Ndjawa Xin Lin Gabriel J. Man YunHui L. Lin Jeni C. Sorli Barry P. Rand Antoine Kahn Gregory D. Scholes Yueh‐Lin Loo 《Liver Transplantation》2019,9(48)
The electron–hole recombination kinetics of organic photovoltaics (OPVs) are known to be sensitive to the relative energies of triplet and charge‐transfer (CT) states. Yet, the role of exciton spin in systems having CT states above 1.7 eV—like those in near‐ultraviolet‐harvesting OPVs—has largely not been investigated. Here, aggregation‐induced room‐temperature intersystem crossing (ISC) to facilitate exciton harvesting in OPVs having CT states as high as 2.3 eV and open‐circuit voltages exceeding 1.6 V is reported. Triplet excimers from energy‐band splitting result in ultrafast CT and charge separation with nonradiative energy losses of <250 meV, suggesting that a 0.1 eV driving force is sufficient for charge separation, with entropic gain via CT state delocalization being the main driver for exciton dissociation and generation of free charges. This finding can inform engineering of next‐generation active materials and films for near‐ultraviolet OPVs with open‐circuit voltages exceeding 2 V. Contrary to general belief, this work reveals that exclusive and efficient ISC need not require heavy‐atom‐containing active materials. Molecular aggregation through thin‐film processing provides an alternative route to accessing 100% triplet states on photoexcitation. 相似文献
6.
R A Kahn 《The Journal of biological chemistry》1991,266(24):15595-15597
Effects of aluminum, magnesium, and fluoride (AMF) on members of both the trimeric G protein and smaller (20-25 kDa) monomeric GTP-binding protein families were examined. The dissociation of GDP from G proteins was blocked by AMF but was unchanged with the addition of AMF to any of six of the monomeric GTP-binding proteins. Biochemical activities and properties of one of the smaller GTP-binding proteins, ADP-ribosylation factor, were also found to be unaffected by AMF. It is concluded that the ability of AMF to activate the trimeric G proteins is not shared by the smaller GTP-binding proteins and thus should prove to be a useful discriminator between cellular activities regulated by these two families of regulatory proteins. 相似文献
7.
J F Decaux O Marcillat A L Pichard J Henry A Kahn 《The Journal of biological chemistry》1991,266(6):3432-3438
8.
Heterogeneity of expression and secretion of native and mutant [AspB10]insulin in AtT20 cells 总被引:2,自引:0,他引:2
S Ferber D J Gross L Villa-Komaroff F Danehy F Vollenweider K Meyer M R Loeken C R Kahn P A Halban 《Molecular endocrinology (Baltimore, Md.)》1991,5(3):319-326
AtT20 (pituitary corticotroph) cells were transfected with either the native or a mutant [AspB10]rat insulin II gene, using a plasmid containing the insulin gene and a neomycin resistance gene under the control of independent constitutive promoters. The cellular immunoreactive insulin (IRI) content ranged from 0.8-440 ng/10(6) cells, with the highest value similar to that found for a rat insulinoma cell line (RIN) and corresponding to approximately 1% that of native pancreatic B-cells. There was a direct correlation between insulin mRNA levels and IRI content and no correlation between mRNA levels and rat insulin II gene copy number. Furthermore, in some lines the insulin II transgene was lost even though the gene encoding neomycin resistance was retained. IRI release was stimulated up to 4-fold by isobutylmethylxanthine in all lines transfected with the native rat insulin II gene, and HPLC analysis showed most IRI as fully processed insulin, with less than 5% as proinsulin. These cells, thus, directed most proinsulin to secretory granules for conversion and regulated release regardless of the absolute amount of IRI expressed. One of the lines transfected with the AspB10 mutant gene (line AA9) released nearly 50% of IRI as proinsulin under basal conditions, with stimulation of insulin, but not proinsulin, release by isobutylmethylxanthine. This confirmed our previous finding of partial diversion of this mutant proinsulin from the regulated to the constitutive pathway. A second line (IC6) expressing the same mutant gene at much higher levels appeared to direct all mutant proinsulin to the regulated pathway, suggesting that for this particular mutant proinsulin, the secretory pathway employed by the transfected cells can be affected by the amount of proinsulin synthesized. 相似文献
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