Computational analysis of molecular basis of 1:1 interactions of NRG-1β wild-type and variants with ErbB3 and ErbB4

2005 ◽  
Vol 59 (4) ◽  
pp. 742-756 ◽  
Author(s):  
Cheng Luo ◽  
Lingfei Xu ◽  
Suxin Zheng ◽  
Xiaomin Luo ◽  
Jianhua Shen ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Computational Analysis ◽  
Wild Type

scholarly journals Acquisition of the Ability To Assimilate Mannitol by Saccharomyces cerevisiae through Dysfunction of the General Corepressor Tup1-Cyc8

2014 ◽  
Vol 81 (1) ◽  
pp. 9-16 ◽  
Author(s):  
Moeko Chujo ◽  
Shiori Yoshida ◽  
Anri Ota ◽  
Kousaku Murata ◽  
Shigeyuki Kawai
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Molecular Basis ◽  
Mutant Allele ◽  
Wild Type ◽  
Growth Data ◽  
Content Type ◽  
Corepressor Complex ◽  
Marine Biomass ◽  
Prolonged Culture ◽  
Genes Encoding

ABSTRACTSaccharomyces cerevisiaenormally cannot assimilate mannitol, a promising brown macroalgal carbon source for bioethanol production. The molecular basis of this inability remains unknown. We found that cells capable of assimilating mannitol arose spontaneously from wild-typeS. cerevisiaeduring prolonged culture in mannitol-containing medium. Based on microarray data, complementation analysis, and cell growth data, we demonstrated that acquisition of mannitol-assimilating ability was due to spontaneous mutations in the genes encoding Tup1 or Cyc8, which constitute a general corepressor complex that regulates many kinds of genes. We also showed that anS. cerevisiaestrain carrying a mutant allele ofCYC8exhibited superior salt tolerance relative to other ethanologenic microorganisms; this characteristic would be highly beneficial for the production of bioethanol from marine biomass. Thus, we succeeded in conferring the ability to assimilate mannitol onS. cerevisiaethrough dysfunction of Tup1-Cyc8, facilitating production of ethanol from mannitol.

scholarly journals Molecular basis of attenuation of neurovirulence of wild-type Japanese encephalitis virus strain SA14

1995 ◽  
Vol 76 (2) ◽  
pp. 409-413 ◽  
Author(s):  
H. Ni ◽  
G.-J. J. Chang ◽  
H. Xie ◽  
D. W. Trent ◽  
A. D. T. Barrett
Keyword(s):  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Virus Strain ◽  
Molecular Basis ◽  
Encephalitis Virus ◽  
Wild Type

scholarly journals Molecular Basis of Ca2+ Activation of the Mouse Cardiac Ca2+ Release Channel (Ryanodine Receptor)

2001 ◽  
Vol 118 (1) ◽  
pp. 33-44 ◽  
Author(s):  
Pin Li ◽  
S.R. Wayne Chen
Keyword(s):  
Lipid Bilayers ◽  
Ryanodine Receptor ◽  
Molecular Basis ◽  
Single Channel ◽  
Single Point ◽  
Hek293 Cells ◽  
Single Point Mutation ◽  
Single Channels ◽  
Wild Type ◽  
Structural And Functional Properties

Activation of the cardiac ryanodine receptor (RyR2) by Ca2+ is an essential step in excitation-contraction coupling in heart muscle. However, little is known about the molecular basis of activation of RyR2 by Ca2+. In this study, we investigated the role in Ca2+ sensing of the conserved glutamate 3987 located in the predicted transmembrane segment M2 of the mouse RyR2. Single point mutation of this conserved glutamate to alanine (E3987A) reduced markedly the sensitivity of the channel to activation by Ca2+, as measured by using single-channel recordings in planar lipid bilayers and by [3H]ryanodine binding assay. However, this mutation did not alter the affinity of [3H]ryanodine binding and the single-channel conductance. In addition, the E3987A mutant channel was activated by caffeine and ATP, was inhibited by Mg2+, and was modified by ryanodine in a fashion similar to that of the wild-type channel. Coexpression of the wild-type and mutant E3987A RyR2 proteins in HEK293 cells produced individual single channels with intermediate sensitivities to activating Ca2+. These results are consistent with the view that glutamate 3987 is a major determinant of Ca2+ sensitivity to activation of the mouse RyR2 channel, and that Ca2+ sensing by RyR2 involves the cooperative action between ryanodine receptor monomers. The results of this study also provide initial insights into the structural and functional properties of the mouse RyR2, which should be useful for studying RyR2 function and regulation in genetically modified mouse models.

scholarly journals Mutations at pipX Suppress Lethality of PII-Deficient Mutants of Synechococcus elongatus PCC 7942

2009 ◽  
Vol 191 (15) ◽  
pp. 4863-4869 ◽  
Author(s):  
Javier Espinosa ◽  
Miguel Angel Castells ◽  
Karim Boumediene Laichoubi ◽  
Asunción Contreras
Keyword(s):  
Molecular Basis ◽  
Synechococcus Elongatus ◽  
Wild Type ◽  
Growth Defects ◽  
Genetic Inactivation ◽  
Domains Of Life ◽  
Synechococcus Elongatus Pcc 7942 ◽  
Pcc 7942 ◽  
Severe Growth ◽  
Null Mutants

ABSTRACT The PII proteins are found in all three domains of life as key integrators of signals reflecting the balance of nitrogen and carbon. Genetic inactivation of PII proteins is typically associated with severe growth defects or death. However, the molecular basis of these defects depends on the specific functions of the proteins with which PII proteins interact to regulate nitrogen metabolism in different organisms. In Synechococcus elongatus PCC 7942, where PII forms complexes with the NtcA coactivator PipX, attempts to engineer PII-deficient strains failed in a wild-type background but were successful in pipX null mutants. Consistent with the idea that PII is essential to counteract the activity of PipX, four different spontaneous mutations in the pipX gene were found in cultures in which glnB had been genetically inactivated.

scholarly journals S19W, T27W, and N330Y mutations in ACE2 enhance SARS-CoV-2 S-RBD binding toward both wild-type and antibody-resistant viruses and its molecular basis

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Fei Ye ◽  
Xi Lin ◽  
Zimin Chen ◽  
Fanli Yang ◽  
Sheng Lin ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Structural Data ◽  
Van Der Waals Interactions ◽  
Side Chains ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Wild Type ◽  
Angiotensin Converting Enzyme 2 ◽  
Domain Protein ◽  
Entry Inhibition

AbstractSARS-CoV-2 recognizes, via its spike receptor-binding domain (S-RBD), human angiotensin-converting enzyme 2 (ACE2) to initiate infection. Ecto-domain protein of ACE2 can therefore function as a decoy. Here we show that mutations of S19W, T27W, and N330Y in ACE2 could individually enhance SARS-CoV-2 S-RBD binding. Y330 could be synergistically combined with either W19 or W27, whereas W19 and W27 are mutually unbeneficial. The structures of SARS-CoV-2 S-RBD bound to the ACE2 mutants reveal that the enhanced binding is mainly contributed by the van der Waals interactions mediated by the aromatic side-chains from W19, W27, and Y330. While Y330 and W19/W27 are distantly located and devoid of any steric interference, W19 and W27 are shown to orient their side-chains toward each other and to cause steric conflicts, explaining their incompatibility. Finally, using pseudotyped SARS-CoV-2 viruses, we demonstrate that these residue substitutions are associated with dramatically improved entry-inhibition efficacy toward both wild-type and antibody-resistant viruses. Taken together, our biochemical and structural data have delineated the basis for the elevated S-RBD binding associated with S19W, T27W, and N330Y mutations in ACE2, paving the way for potential application of these mutants in clinical treatment of COVID-19.

scholarly journals Nucleosomal association and altered interactome underlie the mechanism of cataract caused by the R54C mutation of αA-crystallin

2020 ◽  
Author(s):  
Saad M. Ahsan ◽  
Bakthisaran Raman ◽  
Tangirala Ramakrishna ◽  
Ch. Mohan Rao
Keyword(s):  
Molecular Basis ◽  
Quaternary Structure ◽  
Nuclear Translocation ◽  
Intracellular Localization ◽  
Small Heat Shock Protein ◽  
Chaperone Activity ◽  
Wild Type ◽  
Terminal Domain ◽  
Αb Crystallin ◽  
Arginine Residues

AbstractThe small heat shock protein (sHSP), αA-crystallin, plays an important role in eye lens development. It has three distinct domains viz. the N-terminal domain, α-crystallin domain and the C-terminal extension. While the α-crystallin domain is conserved across the sHSP family, the N-terminal domain and the C-terminal extension are comparatively less conserved. Nevertheless, certain arginine residues in the N-terminal region of αA-crystallin are conserved across the sHSP family. Interestingly, most of the cataractcausing mutations in αA-crystallin occur in the conserved arginine residues. In order to understand the molecular basis of cataract caused by the R54C mutation in human αA-crystallin, we have compared the structure, chaperone activity, intracellular localization, effect on cell viability and “interactome” of wild-type and mutant αA-crystallin. Although R54CαA-crystallin exhibited slight changes in quaternary structure, its chaperone activity was comparable to that of the wild-type. When expressed in lens epithelial cells, R54CαA-crystallin triggered a stress-like response, resulting in nuclear translocation of αB-crystallin, disassembly of cytoskeletal elements and activation of Caspase 3, leading to apoptosis. Comparison of the “interactome” of the wild-type and mutant proteins revealed a striking increase in the interaction of the mutant protein with nucleosomal histones (H2A, H2B, H3 and H4). Using purified chromatin fractions, we show an increased association of R54CαA-crystallin with these nucleosomal histones, suggesting the potential role of the mutant in transcriptional modulation. Thus, the present study shows that alteration of “interactome” and its nucleosomal association, rather than loss of chaperone activity, is the molecular basis of cataract caused by the R54C mutation in αA-crystallin.

scholarly journals Generation and molecular characteristics of a highly attenuated GPV strain through adaptation in GEF cells

2020 ◽  
Author(s):  
Hongxia Shao ◽  
Yuchen Jiang ◽  
Huisha Yuan ◽  
Lifei Ji ◽  
Wenjie Jin ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Wild Type Strain ◽  
Vaccine Candidate ◽  
Molecular Characteristics ◽  
Insertion Mutation ◽  
Wild Type ◽  
Highly Pathogenic ◽  
Mutation Profile ◽  
Molecular Determinants ◽  
Goose Parvovirus

Abstract Background: Goose parvovirus (GPV) has spread globally and causes huge ecomonic loss to poultry industry. Although the attenuated GPV vaccines play vital roles in preventing the disease caused by GPV, the molecular basis for the attenuation of GPV is barely known. Results: A highly attenuated GPV strain GPV-CZM-142 was generated through blindly passaging of the highly pathogenic strain GPV-CZM in goose embryo fibroblasts (GEF) for 142 generations. The virulence of the GEF-adapted GPV strain was 10000 times less than that of the wild type GPV-CZM based on the ELD50. Genome sequencing revealed that a novel insertion in ITR and host adapted mutations in NS and VP1 were found in GPV-CZM-142 in comparison with the wild type strain.Conclusions: The generation of the highly attenuated GPV strain GPV-CZM-142 and the identified virulence-related insertion/mutation profile in the genome not only provided GPV attenuated vaccine candidate, but also gives novel insights into the molecular determinants for GPV attenuation.

scholarly journals Synaptotagmin 1 oligomers clamp and regulate different modes of neurotransmitter release

2019 ◽  
Author(s):  
Erica Tagliatti ◽  
Oscar D. Bello ◽  
Philipe R. F. Mendonça ◽  
Dimitrios Kotzadimitriou ◽  
Elizabeth Nicholson ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Transmitter Release ◽  
Neurotransmitter Release ◽  
Action Potentials ◽  
Molecular Basis ◽  
Activation Mechanism ◽  
Wild Type ◽  
Knock Out ◽  
Synaptotagmin 1 ◽  
Asynchronous Release

AbstractSynaptotagmin1 (Syt1) synchronises neurotransmitter release to action potentials acting as the fast Ca2+ release sensor and as the inhibitor (clamp) of spontaneous and delayed asynchronous release. Whilst the Syt1 Ca2+ activation mechanism has been well characterised, how Syt1 clamps transmitter release remains enigmatic. Here we show that C2B domain-dependent oligomerisation provides the molecular basis for the Syt1 clamping function. This follows from the investigation of a designed mutation (F349A), which selectively destabilises Syt1 oligomerisation. Using combination of fluorescence imaging and electrophysiology in neocortical synapses we show that Syt1F349A is more efficient than wild type Syt1 (Syt1WT) in triggering synchronous transmitter release but fails to clamp spontaneous and Synaptotagmin7 (Syt7)-mediated asynchronous release components both in rescue (Syt1−/− knock-out background) and dominant-interference (Syt1+/+ background) conditions. Thus we conclude that Ca2+-sensitive Syt1 oligomers, acting as an exocytosis clamp, are critical for maintaining the balance among the different modes of neurotransmitter release.

scholarly journals A Single Amino Acid at Residue 188 of Hexon Protein is Responsible for the Pathogenicity of the Emerging Novel Fowl Adenovirus 4

2021 ◽  
Author(s):  
Yu Zhang ◽  
Aijing Liu ◽  
Yanan Wang ◽  
Hongyu Cui ◽  
Yulong Gao ◽  
...  
Keyword(s):  
Amino Acid ◽  
Mutant Strain ◽  
Molecular Basis ◽  
Type Strain ◽  
Wild Type Strain ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Hexon Protein

Since 2015, severe hydropericardium-hepatitis syndrome (HHS) associated with a novel fowl adenovirus 4 (FAdV-4) has emerged in China, representing a new challenge for the poultry industry. Although various highly pathogenic FAdV-4 strains have been isolated, the virulence factor and the pathogenesis of novel FAdV-4 are unclear. In our previous studies, we reported that a large genomic deletion (1966 bp) is not related to increased virulence. In this study, two recombinant chimeric viruses, rHN20 strain and rFB2 strain, were generated from a highly pathogenic FAdV-4 strain by replacing hexon or fiber-2 gene of a non-pathogenic FAdV-4, respectively. Both chimeric strains showed similar titers to the wild type strain in vitro . Notably, rFB2 and the wild type strain induced 100% mortality, while no mortality or clinical signs appeared in chickens inoculated with rHN20, indicating that hexon, but not fiber-2, determines the novel FAdV-4 virulence. Furthermore, an R188I mutation in the hexon protein identified residue 188 as the key amino acid for the reduced pathogenicity. The rR188I mutant strain was significantly neutralized by chicken serum in vitro and in vivo , whereas the wild type strain was able to replicate efficiently. Finally, the immunogenicity of the rescued rR188I was investigated. Non-pathogenic rR188I provided full protection against lethal FAdV-4 challenge. Collectively, these findings provide an in-depth understanding of the molecular basis of novel FAdV-4 pathogenicity and present rR188I as a potential live attenuated vaccine candidate or a novel vaccine vector for HHS vaccines. Importance HHS associated with a novel FAdV-4 infection in chickens has caused huge economic losses to the poultry industry in China since 2015. The molecular basis for the increased virulence remains largely unknown. Here, we demonstrate that the hexon gene is vital for FAdV-4 pathogenicity. Furthermore, we show that the amino acid residue at position 188 of the hexon protein is responsible for pathogenicity. Importantly, the rR188I mutant strain was neutralized by chicken serum in vitro and in vivo , whereas the wild type strain was not. Further, the rR188I mutant strain provided complete protection against FAdV-4 challenge. Our results provide a molecular basis of the increased virulence of novel FAdV-4. We propose that the rR188I mutant is a potential live attenuated vaccine against HHS and a new vaccine vector for HHS-combined vaccines.

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