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2021 ◽  
Vol 118 (18) ◽  
pp. e2017452118
Author(s):  
Xue Yang ◽  
Baifan Wang ◽  
Cody L. Hoop ◽  
Jonathan K. Williams ◽  
Jean Baum

Amyloid fibril formation of α-synuclein (αS) is associated with multiple neurodegenerative diseases, including Parkinson’s disease (PD). Growing evidence suggests that progression of PD is linked to cell-to-cell propagation of αS fibrils, which leads to seeding of endogenous intrinsically disordered monomer via templated elongation and secondary nucleation. A molecular understanding of the seeding mechanism and driving interactions is crucial to inhibit progression of amyloid formation. Here, using relaxation-based solution NMR experiments designed to probe large complexes, we probe weak interactions of intrinsically disordered acetylated-αS (Ac-αS) monomers with seeding-competent Ac-αS fibrils and seeding-incompetent off-pathway oligomers to identify Ac-αS monomer residues at the binding interface. Under conditions that favor fibril elongation, we determine that the first 11 N-terminal residues on the monomer form a common binding site for both fibrils and off-pathway oligomers. Additionally, the presence of off-pathway oligomers within a fibril seeding environment suppresses seeded amyloid formation, as observed through thioflavin-T fluorescence experiments. This highlights that off-pathway αS oligomers can act as an auto-inhibitor against αS fibril elongation. Based on these data taken together with previous results, we propose a model in which Ac-αS monomer recruitment to the fibril is driven by interactions between the intrinsically disordered monomer N terminus and the intrinsically disordered flanking regions (IDR) on the fibril surface. We suggest that this monomer recruitment may play a role in the elongation of amyloid fibrils and highlight the potential of the IDRs of the fibril as important therapeutic targets against seeded amyloid formation.



2021 ◽  
Vol 9 (1) ◽  
pp. 50
Author(s):  
Jiandong Wang ◽  
Jiayuan Zhuang ◽  
Yumin Su ◽  
Xiaosheng Bi

A comparative analysis of the hydrodynamic performance of a planing craft in the monomer-form state (MFS) and trimaran-form state (TFS) was performed, and the inhibition mechanism of twin side-hulls on porpoising instability was evaluated based on the numerical method. A series of drag tests were conducted on the monomer-form models with different longitudinal locations of the center of gravity (Lcg); the occurrence of porpoising and the influence of Lcg on porpoising by the model was discussed. Then, based on the Reynolds-averaged Navier–Stokes (RANS) solver and overset grid technology, numerical simulations of the model were performed, and using test data, the results were verified by incorporating the whisker spray equation of Savitsky. To determine how the porpoising is inhibited in the TFS, simulations for the craft in the MFS and TFS when porpoising were performed and the influence of side-hulls on sailing attitudes and hydrodynamic performance at different speeds were analyzed. Using the full factor design spatial sampling method, the influence of longitudinal and vertical side-hull placements on porpoising inhibition were deliberated, and the optimal side-hull location range is reported and verified on the scale of a real ship. The results indicate that the longitudinal side-hull location should be set in the ratio (a/Lm) range from 0.1 to 0.3, and vertically, the draft ratio (Dd/Tm) should be less than 0.442. Following these recommendations, porpoising instability can be inhibited, and lesser resistance can be achieved.



2016 ◽  
Vol 311 (4) ◽  
pp. H1051-H1062 ◽  
Author(s):  
Tao Bai ◽  
Xinyue Hu ◽  
Yang Zheng ◽  
Shudong Wang ◽  
Jian Kong ◽  
...  

The bacterial endotoxin lipopolysaccharide (LPS) is a main culprit responsible for cardiac dysfunction in sepsis. This study examined whether resveratrol could protect against LPS-induced cardiac dysfunction by improving the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity. Echocardiographic parameters, cardiomyocyte contractile and Ca2+ transient properties, markers for cardiac inflammation, cell death, and oxidative stress, SERCA2a activity, and the ratios of phospholamban (PLB) monomer to oligomer were measured. Cardiac function was decreased >50% after LPS challenge (6 mg/kg for 6 h), which was improved by resveratrol. There was neither difference in plasma tumor necrosis factor-α and troponin I levels nor in infiltration of CD45+ cells in cardiac tissue between resveratrol-treated and untreated groups. In cardiomyocytes, LPS significantly decreased contractile amplitude, elongated relengthening time, diminished Ca2+ transient, reduced SERCA2a activity, and increased superoxide generation. These pathological alterations were attenuated by resveratrol treatment. Immunoblot analysis showed that LPS-treated mice had increased levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and the monomer form of PLB, along with decreases in the levels of SERCA2a, the oligomer form of PLB and nuclear factor erythroid 2-related factor (Nrf-2). Resveratrol treatment upregulated SERCA2a, the oligomer form of PLB, and Nrf-2 expression and function, and downregulated MDA, 4-HNE, and the monomer form of PLB. Our data suggest that the activity of SERCA2a in endotoxemia is inhibited, possibly due to increases in the monomer form of PLB. Resveratrol protects the heart from LPS-induced injuries at least in part through promoting the oligomerization of PLB that leads to enhanced SERCA2a activity.



2016 ◽  
Vol 23 (1) ◽  
pp. 152-157 ◽  
Author(s):  
Takayasu Kawasaki ◽  
Toyonari Yaji ◽  
Toshiaki Ohta ◽  
Koichi Tsukiyama

A mid-infrared free-electron laser (FEL) is a linearly polarized, high-peak powered pulse laser with tunable wavelength within the mid-infrared absorption region. It was recently found that pathogenic amyloid fibrils could be partially dissociated to the monomer form by the irradiation of the FEL targeting the amide I band (C=O stretching vibration), amide II band (N—H bending vibration) and amide III band (C—N stretching vibration). In this study, the irradiation effect of the FEL on keratin aggregate was tested as another model to demonstrate an applicability of the FEL for dissociation of protein aggregates. Synchrotron radiation infrared microscopy analysis showed that the α-helix content in the aggregate structure decreased to almost the same level as that in the monomer state after FEL irradiation tuned to 6.06 µm (amide I band). Both irradiations at 6.51 µm (amide II band) and 8.06 µm (amide III band) also decreased the content of the aggregate but to a lesser extent than for the irradiation at the amide I band. On the contrary, the irradiation tuned to 5.6 µm (non-absorbance region) changed little the secondary structure of the aggregate. Scanning-electron microscopy observation at the submicrometer order showed that the angular solid of the aggregate was converted to non-ordered fragments by the irradiation at each amide band, while the aggregate was hardly deformed by the irradiation at 5.6 µm. These results demonstrate that the amide-specific irradiation by the FEL was effective for dissociation of the protein aggregate to the monomer form.



2015 ◽  
Vol 766-767 ◽  
pp. 3-7 ◽  
Author(s):  
J. Lilly Mercy ◽  
S. Prakash ◽  
Katta Sai Sandeep ◽  
Dasari Sai Praveen

Self-healing composite materials possess healing agent which fills up the crack when ruptured and heals the crack by becoming a tough polymer when stimulated by a catalyst. Dicyclopentadiene (DCPD) in its monomer form is microencapsulated in the shell of Urea Formaldehyde (UF) under different agitation rates to acquire microcapsules of different diameters. The distribution of particle size, surface morphology and the presence of various chemical constituents in the microcapsules were analysed using optical microscopy, SEM and EDAX respectively. An agitation rate of 300 rpm, yielded capsules of diameters ranging from 800μm to 1700μm and at 900rpm the diameters were less than 300μm. Spherical shaped free flowing microcapsules were obtained through insitu polymerisation of dicyclopentadiene in Urea Formaldehyde.



Blood ◽  
2014 ◽  
Vol 123 (12) ◽  
pp. 1785-1793 ◽  
Author(s):  
Yan-Feng Zhou ◽  
Timothy A. Springer

Key Points C-terminal cystine knot monomers in VWF are highly elongated and form antiparallel dimers. Three disulfides across the dimer interface flanked by the cystine knots in each monomer form a highly force-resistant structure.



2014 ◽  
Vol 50 (44) ◽  
pp. 5854-5857 ◽  
Author(s):  
Lok Nath Neupane ◽  
Song Yee Han ◽  
Keun-Hyeung Lee

An amphiphilic dipeptide (1) bearing pyrene and phenylboronic acid was demonstrated as a unique example of a ratiometric sensing system for sugars by reversibly converting the peptide aggregates into the monomer form of the complex with sugars in aqueous solutions.



2013 ◽  
Vol 457 (1) ◽  
pp. 89-97 ◽  
Author(s):  
Jihan Talib ◽  
Jair Kwan ◽  
Aldwin Suryo Rahmanto ◽  
Paul K. Witting ◽  
Michael J. Davies

The smoking-associated oxidant hypothiocyanous acid converts active dimeric endothelial cell nitric oxide synthase into its monomer form, decreases enzyme activity and releases Zn2+. This is ascribed to targeting of the critical Zn2+–thiol cluster by this thiol-specific oxidant.



2012 ◽  
Vol 441 (3) ◽  
pp. 987-998 ◽  
Author(s):  
Genta Ito ◽  
Takeshi Iwatsubo

Mutations in the LRRK2 (leucine-rich repeat kinase 2) gene have been identified in PARK8, a major form of autosomal-dominantly inherited familial Parkinson's disease, although the biochemical properties of LRRK2 are not fully understood. It has been proposed that LRRK2 predominantly exists as a homodimer on the basis of the observation that LRRK2, with a theoretical molecular mass of 280 kDa, migrates at 600 kDa (p600 LRRK2) on native polyacrylamide gels. In the present study, we biochemically re-examined the nature of p600 LRRK2 and found that p600 LRRK2 was fractionated with a single peak at ~272 kDa by ultracentrifugation on a glycerol gradient. In addition, p600 LRRK2 behaved similarly to monomeric proteins upon two-dimensional electrophoretic separation. These results suggested a monomeric composition of p600 LRRK2 within cells. The p600 LRRK2 exhibited kinase activity as well as GTP-binding activity, and forced dimerization of LRRK2 neither upregulated its kinase activity nor altered its subcellular localization. Collectively, we conclude that the monomer form of LRRK2 is predominant within cells, and that dimerization is dispensable for its enzymatic activity.



2010 ◽  
Vol 14 (2) ◽  
pp. 117-126 ◽  
Author(s):  
Yoo-Sup Lee ◽  
Hyun-Suk Ko ◽  
Kyoung-Seok Ryu ◽  
Young-Ho Jeon ◽  
Hyung-Sik Won


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