Structurally restricted Bi(III) metallation of apo-βMT1a: metal-induced tangling

Metallomics ◽  
2021 ◽  
Author(s):  
Natalie C Korkola ◽  
Elyse Hudson ◽  
Martin J Stillman
Keyword(s):  
Metal Binding ◽  
Binding Sites ◽  
Metal Exchange ◽  
Ionization Mass ◽  
Cysteine Modification ◽  
Cross Link ◽  
The Third ◽  
Anti Cancer ◽  
Bismuth Salts ◽  
The Impact

Abstract Non-toxic bismuth salts are used in anti-ulcer medications and to protect against nephrotoxicity from anti-cancer drugs. Bismuth salts also induce metallothionein (MT), a metal-binding protein that lacks a formal secondary structure. We report the impact on the metallation properties of Bi(III) to the 9-cysteine β fragment of MT as a function of cysteine accessibility using electrospray ionization mass spectrometry. At pH 7.4, Bi2βMT formed cooperatively. Cysteine modification shows that each Bi(III) was terminally bound to 3 cysteinyl thiolates. Non-cooperative Bi(III) binding was observed at pH 2.3, where cysteine accessibility is increased. However, competition from H4EDTA inhibited Bi(III) binding. When GdmCl, a well-known denaturing agent, was used to increase cysteine accessibility of the apoβMT at pH 7.4, a greater fraction of Bi3βMT formed using all 9 cysteines. The change in binding profile and equilibrium of Bi2βMT was determined as a function of acidification, which changed as a result of competition with H4EDTA. There was no Bi(III) transfer between Bi2βMT, Cd3βMT, and Zn3βMT. This lack of metal exchange and the resistance towards binding the third Bi(III) suggests a rigidity in the Bi2βMT binding sites that inhibits Bi(III) mobility. These experiments emphasize the conformational control of metallation that results in substantially different metallated products: at pH 7.4 (many cysteines buried) Bi2βMT, whereas at pH 7.4 (all cysteines accessible) enhanced formation of Bi3βMT. These data suggest that the addition of the first 2 Bi(III) cross-link the protein, blocking access to the remaining 3 cysteines for the third Bi(III), as a result of tangle formation.

scholarly journals The metal binding site composition of the cation diffusion facilitator protein MamM cytoplasmic domain impacts its metal responsivity

2020 ◽  
Author(s):  
Shiran Barber-Zucker ◽  
Anat Shahar ◽  
Sofiya Kolusheva ◽  
Raz Zarivach
Keyword(s):  
Metal Binding ◽  
Binding Sites ◽  
Transmembrane Domain ◽  
Metal Cations ◽  
Data Bank ◽  
Cation Diffusion ◽  
Cation Diffusion Facilitator ◽  
Metal Selectivity ◽  
The Impact

AbstractThe cation diffusion facilitator (CDF) is a conserved family of divalent d-block metal cation transporters that extrude these cations selectively from the cytoplasm. CDF proteins are composed of two domains: the transmembrane domain, through which the cations are transported, and a regulatory cytoplasmic C-terminal domain (CTD). Metal binding to the CTD leads to its tighter conformation, and this sequentially promotes conformational change of the transmembrane domain which allows the actual transport of specific metal cations. It was recently shown that the magnetotactic bacterial CDF protein MamM CTD has a role in metal selectivity, as binding of different metal cations exhibits distinctive affinities and conformations. It is yet unclear whether the composition of the CTD binding sites can impact metal selectivity. Here we performed a mutational study of MamM CTD, where we exchanged the metal binding residues with different metal-binding amino acids. Using X-ray crystallography and Trp-fluorescence spectrometry, we studied the impact of the mutations on the CTD conformation in the presence of different metals. Our results reveal that the incorporation of such mutations alters the domain response to metals in vitro, as mutant forms of the CTD bind metals differently in terms of the composition of the binding sites and the CTD conformation.CoordinatesMamM CTD structures have been deposited in the Protein Data Bank under the following accession codes: 6H5V, 6H5M, 6H5U, 6H8G, 6HAO, 6H88, 6H87, 6H8A, 6H89, 6H8D, 6H5K, 6H9Q, 6H84, 6H83, 6HA2, 6H8I, 6H9T, 6H81, 6HAN, 6H85, 6H9P, 6HHS.

Social and political dimension of stigmatization: The development of Natasha and Maria images for immigrants in Istanbul

2016 ◽  
Vol 13 (1) ◽  
pp. 159-168
Author(s):  
Bayram Unal
Keyword(s):  
Public Perception ◽  
Daily Life ◽  
Legal Framework ◽  
State Law ◽  
Migrant Women ◽  
Political Dimension ◽  
Security Forces ◽  
Official Discourse ◽  
The Third ◽  
The Impact

This study aims at understanding how the perceptions about migrants have been created and transferred into daily life as a stigmatization by means of public perception, media and state law implementations.  The focus would be briefly what kind of consequences these perceptions and stigmatization might lead. First section will examine the background of migration to Turkey briefly and make a summary of migration towards Turkey by 90s. Second section will briefly evaluate the preferential legal framework, which constitutes the base for official discourse differentiating the migrants and implementations of security forces that can be described as discriminatory. The third section deals with the impact of perceptions influential in both formation and reproduction of inclusive and exclusive practices towards migrant women. Additionally, impact of public perception in classifying the migrants and migratory processes would be dealt in this section.

ANTI-CANCER COMPOUNDS ISOLATED FROM SOFT CORAL SINULARIA CRUCIATA - ALCYONIIDAE

2012 ◽  
pp. 84-89
Author(s):  
Quoc Hung Vo ◽  
Nguyen Phuong Nhi Doan ◽  
Dinh Quynh Phu Nguyen ◽  
Thi Dieu Tram Ho ◽  
Thi Hoai Nguyen
Keyword(s):  
Mass Spectrometry ◽  
Soft Coral ◽  
Normal Phase ◽  
Ionization Mass ◽  
Medical Field ◽  
Bioactive Substances ◽  
Anti Cancer ◽  
The World ◽  
Pure Compounds ◽  
Layer Chromatography

Objectives: Nowadays, bioactive substances isolated from marine organisms which are abundant and varied in Vietnamese sea attracted more and more the attention of scientists in the world and Vietnam as well. We have studied on soft coral Sinularia cruciata – Alcyoniidae, which has never been studied in Vietnam before, to find substances which are useful in medical field, especially in anti-cancer therapy. Materials and method: Specimens of soft coral Sinularia cruciata were collected from Con Co, Quang Tri province in May 2011. Pure compounds were isolated by using Thin Layer Chromatography; Column Chromatography normal phase and inverse phase; Shephadex LH 20. Structures of them were determined by spectral data of Nuclear Magnetic Resonance (NMR), Electrospray Ionization Mass Spectrometry (ESI-MS). Results & Conclusion: Structures of 4 compounds were identified: (1) 5.8-epidioxycholest-6-en-3-ol (2) Cholesterol (3) 1-O-hexadecyl-glycerol (Chimyl alcohol) (4) Glycerol 1-O-octadecyl ether (Batyl alcohol). The substance (1) was demonstrated to have strong anti-cancer effects in previous study. Key words Sinularia cruciata, Alcyoniidae, 5,8-epidioxycholest-6-en-3-ol, soft coral, cancer.

GABAA receptors: Various stoichiometrics of subunit arrangement in α1β3 and α1β3ε receptors

2018 ◽  
Vol 24 (17) ◽  
pp. 1839-1844 ◽  
Author(s):  
Ahmad Tarmizi Che Has ◽  
Mary Chebib
Keyword(s):  
Central Nervous System ◽  
Gabaa Receptors ◽  
Binding Sites ◽  
New Drugs ◽  
Pharmacological Properties ◽  
Receptor Complex ◽  
The Third ◽  
Γ Subunit ◽  
Subunit Stoichiometry ◽  
The Central Nervous System

GABAA receptors are members of the Cys-loop family of ligand-gated ion channels which mediate most inhibitory neurotransmission in the central nervous system. These receptors are pentameric assemblies of individual subunits, including α1-6, β1-3, γ1-3, δ, ε, π, θ and ρ1-3. The majority of receptors are comprised of α, β and γ or δ subunits. Depending on the subunit composition, the receptors are located in either the synapses or extrasynaptic regions. The most abundant receptors are α1βγ2 receptors, which are activated and modulated by a variety of pharmacologically and clinically unrelated agents such as benzodiazepines, barbiturates, anaesthetics and neurosteroids, all of which bind at distinct binding sites located within the receptor complex. However, compared to αβγ, the binary αβ receptors lack a benzodiazepine α-γ2 interface. In pentameric αβ receptors, the third subunit is replaced with either an α1 or a β3 subunit leading to two distinct receptors that differ in subunit stoichiometry, 2α:3β or 3α:2β. The consequence of this is that 3α:2β receptors contain an α-α interface whereas 2α:3β receptors contain a β-β interface. Apart from the replacement of γ by α1 or β3 in binary receptors, the incorporation of ε subunit into GABAA receptors might be more complicated. As the ε subunit is not only capable of substituting the γ subunit, but also replacing the α/β subunits, receptors with altered stoichiometry and different pharmacological properties are produced. The different subunit arrangement of the receptors potentially constructs novel binding sites which may become new targets of the current or new drugs.

The impact of maternal obesity on fetal adiposity in the third trimester

2010 ◽  
Vol 95 (Supplement 1) ◽  
pp. Fa25-Fa25
Author(s):  
N. Farah ◽  
M. Kennelly ◽  
V. Donnelly ◽  
B. Stuart ◽  
M. Turner
Keyword(s):  
Maternal Obesity ◽  
Third Trimester ◽  
The Third ◽  
The Impact

Law and Economics

2020 ◽  
pp. 84-102
Author(s):  
Daniel B. Kelly
Keyword(s):  
Economic Analysis ◽  
First Generation ◽  
Law And Economics ◽  
Private Law ◽  
Foreseeable Future ◽  
Business Associations ◽  
The Third ◽  
Starting Point ◽  
The Law ◽  
The Impact

This chapter analyzes how law and economics influences private law and how (new) private law is influencing law and economics. It focuses on three generation or “waves” within law and economics and how they approach private law. In the first generation, many scholars took the law as a starting point and attempted to use economic insights to explain, justify, or reform legal doctrines, institutions, and structures. In the second generation, the “law” at times became secondary, with more focus on theory and less focus on doctrines, institutions, and structures. But this generation also relied increasingly on empirical analysis. In the third generation, which includes scholars in the New Private Law (NPL), there has been a resurgence of interest in the law and legal institutions. To be sure, NPL scholars analyze the law using various approaches, with some more and some less predisposed to economic analysis. However, economic analysis will continue to be a major force on private law, including the New Private Law, for the foreseeable future. The chapter considers three foundational private law areas: property, contracts, and torts. For each area, it discusses the major ideas that economic analysis has contributed to private law, and surveys contributions of the NPL. The chapter also looks at the impact of law and economics on advanced private law areas, such as business associations, trusts and estates, and intellectual property.

Merlin cooperates with neurofibromin and Spred1 to suppress the Ras–Erk pathway

2020 ◽  
Author(s):  
Yan Cui ◽  
Lin Ma ◽  
Stephan Schacke ◽  
Jiani C Yin ◽  
Yi-Ping Hsueh ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Binding Sites ◽  
Neurofibromatosis Type ◽  
Kinase Domain ◽  
Erk Pathway ◽  
Suppressor Activity ◽  
The Third ◽  
Tumor Suppressor Activity ◽  
Multiple Signaling

Abstract The Ras–Erk pathway is frequently over-activated in human tumors. Neurofibromatosis type 1 and 2 (NF1, NF2) are characterized by multiple tumors of Schwann cell origin. The NF1 tumor suppressor neurofibromin is a principal Ras-GAP accelerating Ras inactivation, whereas the NF2 tumor suppressor merlin is a scaffold protein coordinating multiple signaling pathways. We have previously reported that merlin interacts with Ras and p120RasGAP. Here, we show that merlin can also interact with the neurofibromin/Spred1 complex via merlin-binding sites present on both proteins. Further, merlin can directly bind to the Ras-binding domain and the kinase domain of Raf1. As the third component of the neurofibromin/Spred1 complex, merlin cannot increase the Ras-GAP activity; rather, it blocks Ras binding to Raf1 by functioning as a ‘selective Ras barrier’. Merlin-deficient Schwann cells require the Ras–Erk pathway activity for proliferation. Accordingly, suppression of the Ras–Erk pathway likely contributes to merlin’s tumor suppressor activity. Taken together, our results, and studies by others, support targeting or co-targeting of this pathway as a therapy for NF2 inactivation-related tumors.

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