scholarly journals Structural study on ligand specificity of human vitamin B12 transporters

2007 ◽  
Vol 403 (3) ◽  
pp. 431-440 ◽  
Author(s):  
Jochen Wuerges ◽  
Silvano Geremia ◽  
Lucio Randaccio
Keyword(s):  
Vitamin B12 ◽  
Electrostatic Interactions ◽  
Intrinsic Factor ◽  
Point Of View ◽  
Tryptophan Residue ◽  
Ligand Specificity ◽  
Binding Assays ◽  
Terminal Domain ◽  
Affinity Constants ◽  
Structural Point

Studies comparing the binding of genuine cobalamin (vitamin B12) to that of its natural or synthetic analogues have long established increasing ligand specificity in the order haptocorrin, transcobalamin and intrinsic factor, the high-affinity binding proteins involved in cobalamin transport in mammals. In the present study, ligand specificity was investigated from a structural point of view, for which comparative models of intrinsic factor and haptocorrin are produced based on the crystal structure of the homologous transcobalamin and validated by results of published binding assays. Many interactions between cobalamin and its binding site in the interface of the two domains are conserved among the transporters. A structural comparison suggests that the determinant of specificity regarding cobalamin ligands with modified nucleotide moiety resides in the β-hairpin motif β3-turn-β4 of the smaller C-terminal domain. In haptocorrin, it provides hydrophobic contacts to the benzimidazole moiety through the apolar regions of Arg357, Trp359 and Tyr362. Together, these large side chains may compensate for the missing nucleotide upon cobinamide binding. Intrinsic factor possesses only the tryptophan residue and transcobalamin only the tyrosine residue, consistent with their low affinity for cobinamide. Relative affinity constants for other analogues are rationalized similarly by analysis of steric and electrostatic interactions with the three transporters. The structures also indicate that the C-terminal domain is the first site of cobalamin-binding since part of the β-hairpin motif is trapped between the nucleotide moiety and the N-terminal domain in the final holo-proteins.

scholarly journals Viroporin activity of SARS-CoV-2 Orf3a and Envelope protein impacts viral pathogenicity

2021 ◽  
Author(s):  
Manish Sarkar ◽  
Paul Etheimer ◽  
Soham Saha
Keyword(s):  
Electrostatic Interactions ◽  
Inflammatory Responses ◽  
Water Channel ◽  
Point Of View ◽  
Alveolar Cells ◽  
E Protein ◽  
Ionic Imbalance ◽  
Cellular Compartments ◽  
Shed Light ◽  
Structural Point

COVID-19 is caused by SARS-CoV-2 which has affected nearly 220 million people worldwide and death toll close to 5 million as of present day. The approved vaccines are lifesaving yet temporary solutions to such a devastating pandemic. Viroporins are important players of the viral life cycle of SARS-Cov-2 and one of the primary determinants of its pathogenesis. We studied the two prominent viroporins of SARS-CoV-2 (i) Orf3a and (ii) Envelope (E) protein from a structural point of view. Orf3a has several hotspots of mutations which has been reported in SARS-CoV-2 with respect to SARS-CoV-1. Mutations in SARS-CoV-2 Orf3a channel forming residues enhances the formation of a prominent the inter-subunit channel, which was not present in the SARS-CoV-1 Orf3a. This enhanced structural feature can be correlated with higher channelling activity in SARS-CoV-2 than in SARS-CoV-1. On the other hand, E protein is one of the most conserved protein among the SARS-CoV proteome. We found that the water molecules form networks of electrostatic interactions with the polar residues in the E protein putative wetted condition while no water channel formation was observed in the putative dewetted condition. This aqueous medium mediates the non-selective translocation of cations thus affecting the ionic homeostasis of the host cellular compartments. This ionic imbalance leads to increased inflammatory response in the host cell. Our results shed light into the mechanism of viroporin action, which can be leveraged for the development of antiviral therapeutics. Furthermore, our results corroborate with previously published transcriptomic data from COVID-19 infected lung alveolar cells where inflammatory responses and molecular regulators directly impacted by ion channelling were upregulated. These observations overlap with transcript upregulation observed in diseases having acute lung injury, pulmonary fibrosis and Acute Respiratory Distress Syndrome (ARDS).

Masonry: the brittle or plastic material?

2019 ◽  
pp. 22-28
Keyword(s):  
Plastic Material ◽  
Experimental Studies ◽  
Point Of View ◽  
Plastic Properties ◽  
Plastic Deformations ◽  
Base Materials ◽  
Stress States ◽  
Creep Deformations ◽  
Structural Point

The results of experimental studies of masonry on the action of dynamic and static (short-term and long-term) loads are presented. The possibility of plastic deformations in the masonry is analyzed for different types of force effects. The falsity of the proposed approach to the estimation of the coefficient of plasticity of masonry, taking into account the ratio of elastic and total deformations of the masonry is noted. The study of the works of Soviet scientists revealed that the masonry under the action of seismic loads refers to brittle materials in the complete absence of plastic properties in it in the process of instantaneous application of forces. For the cases of uniaxial and plane stress states of the masonry, data on the coefficient of plasticity obtained from the experiment are presented. On the basis of experimental studies the influence of the strength of the so-called base materials (brick, mortar) on the bearing capacity of the masonry, regardless of the nature of the application of forces and the type of its stress state, is noted. The analysis of works of prof. S. V. Polyakov makes it possible to draw a conclusion that at the long application of the load, characteristic for the masonry are not plastic deformations, but creep deformations. It is shown that the proposals of some authors on the need to reduce the level of adhesion of the mortar to the brick for the masonry erected in earthquake-prone regions in order to improve its plastic properties are erroneous both from the structural point of view and from the point of view of ensuring the seismic resistance of structures. It is noted that the proposal to assess the plasticity of the masonry of ceramic brick walls and large-format ceramic stone with a voidness of more than 20% is incorrect, and does not meet the work of the masonry of hollow material. On the basis of the analysis of a large number of research works it is concluded about the fragile work of masonry.

Crimes against marriage and family before Criminal Code 1968

2020 ◽  
Vol 15 (1-3) ◽  
pp. 44-59
Author(s):  
Lidia Peneva
Keyword(s):  
Criminal Code ◽  
Point Of View ◽  
Marriage And Family ◽  
Historical Method ◽  
Legal Method ◽  
The Subject ◽  
The Republic ◽  
Criminal Groups ◽  
The Moment ◽  
Structural Point

Crimes against marriage and family are a particular group of social relation­ships that the law has defended properly in view of the high public significance and value they enjoy. At the moment they are regulated in Chapter VI, Section I, of the specific part of the Penal Code the Repub­lic of Bulgaria. The subject matter of this Statement will, however, be the legisla­tive provisions concerning these criminal­ized acts in retrospect. The purpose of the study is to show by historical method and through the comparatively legal method the development of these criminal groups during the periods of various criminal laws in Bulgaria. This will also provide a basis for reflection on possible de lege ferenda proposals. This report from a structural point of view will be divided into three distinct points, marking each of the penal laws in the Republic of Bulgaria, which were in force before 1968.

Cubilin, the Intrinsic Factor-Vitamin B12 Receptor in Development and Disease

2020 ◽  
Vol 27 (19) ◽  
pp. 3123-3150 ◽  
Author(s):  
Renata Kozyraki ◽  
Olivier Cases
Keyword(s):  
Vitamin B12 ◽  
Cancer Progression ◽  
Intrinsic Factor ◽  
Basic Research ◽  
Toxic Substances ◽  
Human Pathology ◽  
Peripheral Membrane Protein ◽  
Epidermal Growth ◽  
Fgf8 Signaling

Gp280/Intrinsic factor-vitamin B12 receptor/Cubilin (CUBN) is a large endocytic receptor serving multiple functions in vitamin B12 homeostasis, renal reabsorption of protein or toxic substances including albumin, vitamin D-binding protein or cadmium. Cubilin is a peripheral membrane protein consisting of 8 Epidermal Growth Factor (EGF)-like repeats and 27 CUB (defined as Complement C1r/C1s, Uegf, BMP1) domains. This structurally unique protein interacts with at least two molecular partners, Amnionless (AMN) and Lrp2/Megalin. AMN is involved in appropriate plasma membrane transport of Cubilin whereas Lrp2 is essential for efficient internalization of Cubilin and its ligands. Observations gleaned from animal models with Cubn deficiency or human diseases demonstrate the importance of this protein. In this review addressed to basic research and medical scientists, we summarize currently available data on Cubilin and its implication in renal and intestinal biology. We also discuss the role of Cubilin as a modulator of Fgf8 signaling during embryonic development and propose that the Cubilin-Fgf8 interaction may be relevant in human pathology, including in cancer progression, heart or neural tube defects. We finally provide experimental elements suggesting that some aspects of Cubilin physiology might be relevant in drug design.

scholarly journals Recuperative Amino Acids Separation through Cellulose Derivative Membranes with Microporous Polypropylene Fiber Matrix

Membranes ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 429
Author(s):  
Aurelia Cristina Nechifor ◽  
Andreia Pîrțac ◽  
Paul Constantin Albu ◽  
Alexandra Raluca Grosu ◽  
Florina Dumitru ◽  
...  
Keyword(s):  
Amino Acids ◽  
Cellulose Acetate ◽  
Polypropylene Fiber ◽  
Point Of View ◽  
Hydroxyethyl Cellulose ◽  
Separation Performance ◽  
Thermal Gravimetric Analyzer ◽  
Microfiltration Membranes ◽  
Ft Ir ◽  
Structural Point

The separation, concentration and transport of the amino acids through membranes have been continuously developed due to the multitude of interest amino acids of interest and the sources from which they must be recovered. At the same time, the types of membranes used in the sepa-ration of the amino acids are the most diverse: liquids, ion exchangers, inorganic, polymeric or composites. This paper addresses the recuperative separation of three amino acids (alanine, phe-nylalanine, and methionine) using membranes from cellulosic derivatives in polypropylene ma-trix. The microfiltration membranes (polypropylene hollow fibers) were impregnated with solu-tions of some cellulosic derivatives: cellulose acetate, 2-hydroxyethyl-cellulose, methyl 2-hydroxyethyl-celluloseand sodium carboxymethyl-cellulose. The obtained membranes were characterized in terms of the separation performance of the amino acids considered (retention, flux, and selectivity) and from a morphological and structural point of view: scanning electron microscopy (SEM), high resolution SEM (HR-SEM), Fourier transform infrared spectroscopy (FT-IR), energy dispersive spectroscopy (EDS) and thermal gravimetric analyzer (TGA). The re-sults obtained show that phenylalanine has the highest fluxes through all four types of mem-branes, followed by methionine and alanine. Of the four kinds of membrane, the most suitable for recuperative separation of the considered amino acids are those based on cellulose acetate and methyl 2-hydroxyethyl-cellulose.

Divalent cations and vitamin B12 uptake by intestinal brush-border membrane vesicles

1980 ◽  
Vol 239 (6) ◽  
pp. G452-G456
Author(s):  
R. C. Beesley ◽  
C. D. Bacheller
Keyword(s):  
Vitamin B12 ◽  
Brush Border ◽  
Brush Border Membrane ◽  
Divalent Cations ◽  
Intrinsic Factor ◽  
Membrane Vesicles ◽  
Brush Border Membrane Vesicles ◽  
Tetraacetic Acid ◽  
Intestinal Brush Border Membrane ◽  
Intestinal Brush Border

Brush-border membrane vesicles from hamster intestine were employed to investigate uptake (binding) of vitamin B12 (B12). Ileal vesicles took up 25 times more B12 than did jejunal vesicles. Uptake of B12 by ileal vesicles was dependent on intrinsic factor (IF) and required Ca2+. Increasing the Ca2+ concentration caused an increase in uptake of B12 reaching a maximum at approximately 8 mM Ca2+. At high Ca2+ concentrations, 6–8 mM, Mg2+ had little effect on uptake of B12. At low Ca2+ concentrations, up to 2 mM, Mg2+ stimulated B12 uptake. Mg2+, Mn2+, and, to a lesser extent, Sr2+ stimulated Ca2+-dependent B12 uptake, but Zn2+, Ba2+, Na+, K+, and La3+ did not. B12 was apparently not metabolized and was bound as IF-B12 complex, which could be removed with (ethylenedinitrilo)tetraacetic acid (EDTA). Our results suggest that two types of divalent cation reactive sites are involved in binding of IF-B12. One is Ca2+ specific. The other is less specific reacting with Mg2+, Mn2+, Sr2+, and perhaps Ca2+ itself, thereby stimulating Ca2+-dependent binding of IF-B12 to its ileal receptor.

scholarly journals Crystallographic and structural characterization of heterometallic platinum compounds Part VII. Heterohepta- and heterooctanuclear clusters

2014 ◽  
Vol 13 (1) ◽  
Author(s):  
Milan Melnik ◽  
Peter Mikuš ◽  
Clive E. Holloway
Keyword(s):  
Structural Characterization ◽  
Structural Parameters ◽  
Bond Distance ◽  
Point Of View ◽  
Platinum Compounds ◽  
Metal Atoms ◽  
Platinum Clusters ◽  
Structural Point

AbstractThis review classifies and analyzes over fifty heterohepta- and heterooctanuclear platinum clusters. There are eight types of metal combinations in heteroheptanuclear: Pt6M, Pt5M2, Pt4M3, Pt3M4, Pt2M5, PtM6, Pt3Hg2Ru2 and Pt2Os3Fe2. The seven metal atoms are in a wide variety of arrangements, with the most common being one in which the central M atom (mostly M(I)) is sandwiched by two M3 triangles. Another arrangement often found is an octahedron of M6 atoms asymmetrically capped by an M atom. The shortest Pt-M bond distances (non-transition and transition) are 2.326(1) Å (M = Ga) and 2.537(6) Å (M = Fe). The shortest Pt-Pt bond distance is 2.576(2) Å.In heterooctanuclear platinum clusters there are eight types of metal combinations: Pt6M2, Pt4M4, Pt3Ru5, Pt2M6, PtM7, Pt2W4Ni2, PtAu6Hg and PtAu5Hg2. From a structural point of view, the clusters are complex with bicapped octahedrons of eight metal atoms prevailing. The shortest Pt-M bond distances (non-transition and transition) are 2.651(3) Å (M = Hg) and 2.624(1) Å (M = Os). The shortest Pt-Pt bond distance is 2.622(1) Å. These values are somewhat longer than those in the heteroheptanuclear clusters. Several relationships between the structural parameters were found, and are discussed and compared with the smaller heterometallic platinum clusters

scholarly journals β-Catenin Binds to the Activation Function 2 Region of the Androgen Receptor and Modulates the Effects of the N-Terminal Domain and TIF2 on Ligand-Dependent Transcription

2003 ◽  
Vol 23 (5) ◽  
pp. 1674-1687 ◽  
Author(s):  
Liang-Nian Song ◽  
Roger Herrell ◽  
Stephen Byers ◽  
Salimuddin Shah ◽  
Elizabeth M. Wilson ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Hormone Receptors ◽  
Nuclear Translocation ◽  
Retinoic Acid Receptor ◽  
Activation Function ◽  
Steroid Hormone Receptors ◽  
Binding Assays ◽  
Peptide Motifs ◽  
Terminal Domain ◽  
Helix 12

ABSTRACT β-Catenin is a multifunctional molecule that is activated by signaling through WNT receptors. β-Catenin can also enhance the transcriptional activity of some steroid hormone receptors such as the androgen receptor and retinoic acid receptor α. Androgens can affect nuclear translocation of β-catenin and influence its subcellular distribution. Using mammalian two-hybrid binding assays, analysis of reporter gene transcription, and coimmunoprecipitation, we now show that β-catenin binds to the androgen receptor ligand-binding domain (LBD) and modulates the transcriptional effects of TIF2 and the androgen receptor N-terminal domain (NTD). In functional assays, β-catenin bound to androgen receptor only in the presence of ligand agonists, not antagonists. β-Catenin binding to the androgen receptor LBD was independent of and cooperative with the androgen receptor NTD and the p160 coactivator TIF2, both of which bind to the activation function 2 (AF-2) region of the androgen receptor. Different mutations of androgen receptor helix 3 amino acids disrupted binding of androgen receptor NTD and β-catenin. β-Catenin, androgen receptor NTD, and TIF2 binding to the androgen receptor LBD were affected similarly by a subset of helix 12 mutations, but disruption of two sites on helix 12 affected only binding of β-catenin and not of TIF2 or the androgen receptor NTD. Mutational disruption of each of five LXXLL peptide motifs in the β-catenin armadillo repeats did not disrupt either binding to androgen receptor or transcriptional coactivation. ICAT, an inhibitor of T-cell factor 4 (TCF-4), and E-cadherin binding to β-catenin also blocked binding of the androgen receptor LBD. We also demonstrated cross talk between the WNT and androgen receptor signaling pathways because excess androgen receptor could interfere with WNT signaling and excess TCF-4 inhibited the interaction of β-catenin and androgen receptor. Taken together, the data show that β-catenin can bind to the androgen receptor LBD and modulate the effects of the androgen receptor NTD and TIF2 on transcription.

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