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1.
Some of the most perplexing disorders in medicine are each now known to arise from the conformational instability of an underlying protein. The consequence is a continuum of pathologies with typically a change in fold leading to ordered aggregation and tissue deposition. The serpins provide a structural prototype for these pathologies and give a perspective on the assessment of current proposals as to the conformational basis of both Alzheimer's disease and the transmissible prion encephalopathies. 相似文献
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An integrative approach combining ion mobility mass spectrometry,X-ray crystallography,and nuclear magnetic resonance spectroscopy to study the conformational dynamics of α1-antitrypsin upon ligand binding
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Mun Peak Nyon Tanya Prentice Jemma Day John Kirkpatrick Ganesh N Sivalingam Geraldine Levy Imran Haq James A Irving David A Lomas John Christodoulou Bibek Gooptu Konstantinos Thalassinos 《Protein science : a publication of the Protein Society》2015,24(8):1301-1312
Native mass spectrometry (MS) methods permit the study of multiple protein species within solution equilibria, whereas ion mobility (IM)-MS can report on conformational behavior of specific states. We used IM-MS to study a conformationally labile protein (α1-antitrypsin) that undergoes pathological polymerization in the context of point mutations. The folded, native state of the Z-variant remains highly polymerogenic in physiological conditions despite only minor thermodynamic destabilization relative to the wild-type variant. Various data implicate kinetic instability (conformational lability within a native state ensemble) as the basis of Z α1-antitrypsin polymerogenicity. We show the ability of IM-MS to track such disease-relevant conformational behavior in detail by studying the effects of peptide binding on α1-antitrypsin conformation and dynamics. IM-MS is, therefore, an ideal platform for the screening of compounds that result in therapeutically beneficial kinetic stabilization of native α1-antitrypsin. Our findings are confirmed with high-resolution X-ray crystallographic and nuclear magnetic resonance spectroscopic studies of the same event, which together dissect structural changes from dynamic effects caused by peptide binding at a residue-specific level. IM-MS methods, therefore, have great potential for further study of biologically relevant thermodynamic and kinetic instability of proteins and provide rapid and multidimensional characterization of ligand interactions of therapeutic interest.PDB Code(s): 4PYW 相似文献
3.
Imran Haq James?A. Irving Sarah?V. Faull Jennifer?A. Dickens Adriana Ordó?ez Didier Belorgey Bibek Gooptu David?A. Lomas 《Bioscience reports》2013,33(3)
The common severe Z mutation (E342K) of α1-antitrypsin forms intracellular polymers that are associated with liver cirrhosis. The native fold of this protein is well-established and models have been proposed from crystallographic and biophysical data for the stable inter-molecular configuration that terminates the polymerization pathway. Despite these molecular ‘snapshots’, the details of the transition between monomer and polymer remain only partially understood. We surveyed the RCL (reactive centre loop) of α1-antitrypsin to identify sites important for progression, through intermediate states, to polymer. Mutations at P14P12 and P4, but not P10P8 or P2P1′, resulted in a decrease in detectable polymer in a cell model that recapitulates the intracellular polymerization of the Z variant, consistent with polymerization from a near-native conformation. We have developed a FRET (Förster resonance energy transfer)-based assay to monitor polymerization in small sample volumes. An in vitro assessment revealed the position-specific effects on the unimolecular and multimolecular phases of polymerization: the P14P12 region self-inserts early during activation, while the interaction between P6P4 and β-sheet A presents a kinetic barrier late in the polymerization pathway. Correspondingly, mutations at P6P4, but not P14P12, yield an increase in the overall apparent activation energy of association from ~360 to 550 kJ mol−1. 相似文献
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Mahasweta Saha Francisco R. Barboza Paul J. Somerfield Balsam Al‐Janabi Miriam Beck Janina Brakel Maysa Ito Christian Pansch Jennifer C. Nascimento‐Schulze Stina Jakobsson Thor Florian Weinberger Yvonne Sawall 《Global Change Biology》2020,26(2):417-430
Marine heatwaves have been observed worldwide and are expected to increase in both frequency and intensity due to climate change. Such events may cause ecosystem reconfigurations arising from species range contraction or redistribution, with ecological, economic and social implications. Macrophytes such as the brown seaweed Fucus vesiculosus and the seagrass Zostera marina are foundation species in many coastal ecosystems of the temperate northern hemisphere. Hence, their response to extreme events can potentially determine the fate of associated ecosystems. Macrophyte functioning is intimately linked to the maintenance of photosynthesis, growth and reproduction, and resistance against pathogens, epibionts and grazers. We investigated morphological, physiological, pathological and chemical defence responses of western Baltic Sea F. vesiculosus and Z. marina populations to simulated near‐natural marine heatwaves. Along with (a) the control, which constituted no heatwave but natural stochastic temperature variability (0HW), two treatments were applied: (b) two late‐spring heatwaves (June, July) followed by a summer heatwave (August; 3HW) and (c) a summer heatwave only (1HW). The 3HW treatment was applied to test whether preconditioning events can modulate the potential sensitivity to the summer heatwave. Despite the variety of responses measured in both species, only Z. marina growth was impaired by the accumulative heat stress imposed by the 3HW treatment. Photosynthetic rate, however, remained high after the last heatwave indicating potential for recovery. Only epibacterial abundance was significantly affected in F. vesiculosus. Hence both macrophytes, and in particular F. vesiculosus, seem to be fairly tolerant to short‐term marine heatwaves at least at the intensities applied in this experiment (up to 5°C above mean temperature over a period of 9 days). This may partly be due to the fact that F. vesiculosus grows in a highly variable environment, and may have a high phenotypic plasticity. 相似文献
6.
TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration
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Girgenrath M Weng S Kostek CA Browning B Wang M Brown SA Winkles JA Michaelson JS Allaire N Schneider P Scott ML Hsu YM Yagita H Flavell RA Miller JB Burkly LC Zheng TS 《The EMBO journal》2006,25(24):5826-5839
Inflammation participates in tissue repair through multiple mechanisms including directly regulating the cell fate of resident progenitor cells critical for successful regeneration. Upon surveying target cell types of the TNF ligand TWEAK, we observed that TWEAK binds to all progenitor cells of the mesenchymal lineage and induces NF-kappaB activation and the expression of pro-survival, pro-proliferative and homing receptor genes in the mesenchymal stem cells, suggesting that this pro-inflammatory cytokine may play an important role in controlling progenitor cell biology. We explored this potential using both the established C2C12 cell line and primary mouse muscle myoblasts, and demonstrated that TWEAK promoted their proliferation and inhibited their terminal differentiation. By generating mice deficient in the TWEAK receptor Fn14, we further showed that Fn14-deficient primary myoblasts displayed significantly reduced proliferative capacity and altered myotube formation. Following cardiotoxin injection, a known trigger for satellite cell-driven skeletal muscle regeneration, Fn14-deficient mice exhibited reduced inflammatory response and delayed muscle fiber regeneration compared with wild-type mice. These results indicate that the TWEAK/Fn14 pathway is a novel regulator of skeletal muscle precursor cells and illustrate an important mechanism by which inflammatory cytokines influence tissue regeneration and repair. Coupled with our recent demonstration that TWEAK potentiates liver progenitor cell proliferation, the expression of Fn14 on all mesenchymal lineage progenitor cells supports a broad involvement of this pathway in other tissue injury and disease settings. 相似文献
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The authors describe an unusual form of phase walk (i.e., a progressive change in phase angle between coupled oscillators) using the 10-Hz rhythmic discharges of the inferior cardiac and vertebral postganglionic sympathetic nerves (CN and VN, respectively) in hypercapnic, baroreceptor-denervated, and vagotomized cats anesthetized with urethane. Unlike phase walk ascribable to weakened coupling (desynchronization of oscillators), the phase walk of VN 10- Hz activity relative to CN10-Hz activity 1) recurred on the time scale of the respiratory cycle, 2) was bidirectional with CN-VN phase angle increasing during expiration and decreasing during inspiration, and 3) occurred over a range equivalent to one-half the period of the 10-Hz rhythm rather than a full cycle. Moreover, this form of phase walk occurred during strong coupling of the 10-Hz oscillators, as reflected by CN-VN coherence values approaching 1.0. The authors propose that the bidirectional phase walk reflects a state of strong coupling of the 10-Hz oscillators controlling the CN and VN, the angle of which is reset from cycle to cycle by the continuously changing level of activity in their respiratory inputs. In addition, the data demonstrate that frequency and amplitude modulation of sympathetic nerve discharge can be independently regulated by respiratory inputs. 相似文献
8.
Ajay Kumar Anthony Accorsi Younghwa Rhee Mahasweta Girgenrath 《Journal of visualized experiments : JoVE》2015,(99)
Histological evaluation of muscle biopsies has served as an indispensable tool in the understanding of the development and progression of pathology of neuromuscular disorders. However, in order to do so, proper care needs to be taken when excising and preserving tissues to achieve optimal staining. One method of tissue preservation involves fixing tissues in formaldehyde and then embedding them with paraffin wax. This method preserves morphology well and allows for long-term storage at RT but is cumbersome and requires handling of toxic chemicals. Further, formaldehyde fixation results in antigen cross-linking, which necessitates antigen retrieval protocols for effective immunostaining. On the contrary, frozen sectioning does not require fixation and thus retains biological antigen conformation. This method also provides a distinct advantage in quick turn around time, making it especially useful in situations needing quick histological evaluation like intraoperative surgical biopsies. Here we describe the most effective method of preparing muscle biopsies for visualization with different histological and immunological stains. 相似文献
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Francisco R. Barboza Jonne Kotta Florian Weinberger Veijo Jormalainen Patrik Kraufvelin Markus Molis Hendrik Schubert Henrik Pavia Gran M. Nylund Lena Kautsky Ellen Schagerstrm Esther Rickert Mahasweta Saha Stein Fredriksen Georg Martin Kaire Torn Ari Ruuskanen Martin Wahl 《Ecology and evolution》2019,9(16):9225-9238
In the course of the ongoing global intensification and diversification of human pressures, the study of variation patterns of biological traits along environmental gradients can provide relevant information on the performance of species under shifting conditions. The pronounced salinity gradient, co‐occurrence of multiple stressors, and accelerated rates of change make the Baltic Sea and its transition to North Sea a suitable region for this type of study. Focusing on the bladderwrack Fucus vesiculosus, one of the main foundation species on hard‐bottoms of the Baltic Sea, we analyzed the phenotypic variation among populations occurring along 2,000 km of coasts subjected to salinities from 4 to >30 and a variety of other stressors. Morphological and biochemical traits, including palatability for grazers, were recorded at 20 stations along the Baltic Sea and four stations in the North Sea. We evaluated in a common modeling framework the relative contribution of multiple environmental drivers to the observed trait patterns. Salinity was the main and, in some cases, the only environmental driver of the geographic trait variation in F. vesiculosus. The decrease in salinity from North Sea to Baltic Sea stations was accompanied by a decline in thallus size, photosynthetic pigments, and energy storage compounds, and affected the interaction of the alga with herbivores and epibiota. For some traits, drivers that vary locally such as wave exposure, light availability or nutrient enrichment were also important. The strong genetic population structure in this macroalgae might play a role in the generation and maintenance of phenotypic patterns across geographic scales. In light of our results, the desalination process projected for the Baltic Sea could have detrimental impacts on F. vesiculosus in areas close to its tolerance limit, affecting ecosystem functions such as habitat formation, primary production, and food supply. 相似文献
10.
Young Kwang Chae Stefan Neagu Jongoh Kim Athanasios Smyrlis Mahasweta Gooptu William Tester 《PloS one》2012,7(9)