The Biological Regulation of Copper Homeostasis in the Rat1

2015 ◽  
pp. 225-249 ◽  
Author(s):  
G. W. Evans
Keyword(s):  
Copper Homeostasis ◽  
Biological Regulation

scholarly journals Pharmacological inactivation of the prion protein by targeting a folding intermediate

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Giovanni Spagnolli ◽  
Tania Massignan ◽  
Andrea Astolfi ◽  
Silvia Biggi ◽  
Marta Rigoli ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Surface Glycoprotein ◽  
Folding Intermediate ◽  
Biological Regulation ◽  
Cell Surface Glycoprotein ◽  
Folding Intermediates ◽  
Protein Levels ◽  
Small Molecule Ligands

AbstractRecent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. These techniques allowed us to design a drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein levels by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP and identified four different small molecule ligands for this conformer, all capable of selectively lowering the load of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression.

scholarly journals XIAP: Cell death regulation meets copper homeostasis

2007 ◽  
Vol 463 (2) ◽  
pp. 168-174 ◽  
Author(s):  
Arjmand R. Mufti ◽  
Ezra Burstein ◽  
Colin S. Duckett
Keyword(s):  
Cell Death ◽  
Copper Homeostasis

scholarly journals Primary structure of two P-type ATPases involved in copper homeostasis in Enterococcus hirae

1993 ◽  
Vol 268 (17) ◽  
pp. 12775-12779 ◽  
Author(s):  
A. Odermatt ◽  
H. Suter ◽  
R. Krapf ◽  
M. Solioz
Keyword(s):  
Primary Structure ◽  
Copper Homeostasis ◽  
Enterococcus Hirae ◽  
P Type

scholarly journals Overlapping but distinct: a new model for G-quadruplex biochemical specificity

2021 ◽  
Author(s):  
Martin Volek ◽  
Sofia Kolesnikova ◽  
Katerina Svehlova ◽  
Pavel Srb ◽  
Ráchel Sgallová ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Drug Design ◽  
Solution Structure ◽  
Biochemical Data ◽  
Biological Regulation ◽  
New Model ◽  
G Quadruplex ◽  
Range Of Functions ◽  
Nucleic Acid Structures ◽  
Sequence Requirements

Abstract G-quadruplexes are noncanonical nucleic acid structures formed by stacked guanine tetrads. They are capable of a range of functions and thought to play widespread biological roles. This diversity raises an important question: what determines the biochemical specificity of G-quadruplex structures? The answer is particularly important from the perspective of biological regulation because genomes can contain hundreds of thousands of G-quadruplexes with a range of functions. Here we analyze the specificity of each sequence in a 496-member library of variants of a reference G-quadruplex with respect to five functions. Our analysis shows that the sequence requirements of G-quadruplexes with these functions are different from one another, with some mutations altering biochemical specificity by orders of magnitude. Mutations in tetrads have larger effects than mutations in loops, and changes in specificity are correlated with changes in multimeric state. To complement our biochemical data we determined the solution structure of a monomeric G-quadruplex from the library. The stacked and accessible tetrads rationalize why monomers tend to promote a model peroxidase reaction and generate fluorescence. Our experiments support a model in which the sequence requirements of G-quadruplexes with different functions are overlapping but distinct. This has implications for biological regulation, bioinformatics, and drug design.

scholarly journals Advances in Understanding of the Copper Homeostasis in Pseudomonas aeruginosa

2021 ◽  
Vol 22 (4) ◽  
pp. 2050
Author(s):  
Lukas Hofmann ◽  
Melanie Hirsch ◽  
Sharon Ruthstein
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Pathogenic Bacteria ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Copper Homeostasis ◽  
The United States ◽  
World Health ◽  
Cross Resistance ◽  
Metabolism Regulation ◽  
Target Sites

Thirty-five thousand people die as a result of more than 2.8 million antibiotic-resistant infections in the United States of America per year. Pseudomonas aeruginosa (P. aeruginosa) is classified a serious threat, the second-highest threat category of the U.S. Department of Health and Human Services. Among others, the World Health Organization (WHO) encourages the discovery and development of novel antibiotic classes with new targets and mechanisms of action without cross-resistance to existing classes. To find potential new target sites in pathogenic bacteria, such as P. aeruginosa, it is inevitable to fully understand the molecular mechanism of homeostasis, metabolism, regulation, growth, and resistances thereof. P. aeruginosa maintains a sophisticated copper defense cascade comprising three stages, resembling those of public safety organizations. These stages include copper scavenging, first responder, and second responder. Similar mechanisms are found in numerous pathogens. Here we compare the copper-dependent transcription regulators cueR and copRS of Escherichia coli (E. coli) and P. aeruginosa. Further, phylogenetic analysis and structural modelling of mexPQ-opmE reveal that this efflux pump is unlikely to be involved in the copper export of P. aeruginosa. Altogether, we present current understandings of the copper homeostasis in P. aeruginosa and potential new target sites for antimicrobial agents or a combinatorial drug regimen in the fight against multidrug resistant pathogens.

scholarly journals Time-resolved observation of protein allosteric communication

2017 ◽  
Vol 114 (33) ◽  
pp. E6804-E6811 ◽  
Author(s):  
Sebastian Buchenberg ◽  
Florian Sittel ◽  
Gerhard Stock
Keyword(s):  
Pdz Domain ◽  
Dynamic Network ◽  
Structural Heterogeneity ◽  
Nonequilibrium Molecular Dynamics ◽  
Elastic Response ◽  
Dynamical Process ◽  
Biological Regulation ◽  
Time Resolved ◽  
Allosteric Communication ◽  
Time Resolved Infrared Spectroscopy

Allostery represents a fundamental mechanism of biological regulation that is mediated via long-range communication between distant protein sites. Although little is known about the underlying dynamical process, recent time-resolved infrared spectroscopy experiments on a photoswitchable PDZ domain (PDZ2S) have indicated that the allosteric transition occurs on multiple timescales. Here, using extensive nonequilibrium molecular dynamics simulations, a time-dependent picture of the allosteric communication in PDZ2S is developed. The simulations reveal that allostery amounts to the propagation of structural and dynamical changes that are genuinely nonlinear and can occur in a nonlocal fashion. A dynamic network model is constructed that illustrates the hierarchy and exceeding structural heterogeneity of the process. In compelling agreement with experiment, three physically distinct phases of the time evolution are identified, describing elastic response (≲0.1 ns), inelastic reorganization (∼100 ns), and structural relaxation (≳1μs). Issues such as the similarity to downhill folding as well as the interpretation of allosteric pathways are discussed.

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