scholarly journals Topology and cooperative stability: the two master regulators of protein half-life in the cell

2017 ◽  
Author(s):  
Saurav Mallik ◽  
Sudip Kundu
Keyword(s):  
Molecular Marker ◽  
Self Assembly ◽  
Half Life ◽  
Mechanical Resistance ◽  
Structural Constraints ◽  
Subunit Dissociation ◽  
Master Regulators ◽  
Oligomeric Protein ◽  
Structural Divergence ◽  
Genome Scale

AbstractIn a quest for finding additional structural constraints, apart from disordered segments, regulating protein half-life in the cell (and during evolution), here we recognize and assess the influence of native topology of biological proteins and their sequestration into multimeric complexes. Native topology acts as a molecular marker of protein’s mechanical resistance and consequently captures their half-life variations on genome-scale, irrespective of the enormous sequence, structural and functional diversity of the proteins. Cooperative stability (slower degradation upon sequestration into complexes) is a master regulator of oligomeric protein half-life that involves at least three mechanisms. (i) Association with multiple complexes results longer protein half-life; (ii) hierarchy of complex self-assembly involves short-living proteins binding late in the assembly order and (iii) binding with larger buried surface area leads to slower subunit dissociation and thereby longer half-life. Altered half-lives of paralog proteins refer to their structural divergence and oligomerization with non-identical set of complexes.

scholarly journals Genome-scale actions of master regulators directing skeletal development

2021 ◽  
Vol 57 ◽  
pp. 217-223
Author(s):  
Shinsuke Ohba
Keyword(s):  
Skeletal Development ◽  
Master Regulators ◽  
Genome Scale

scholarly journals Coessential Genetic Networks Reveal the Organization and Constituents of a Dynamic Cellular Stress Response

2019 ◽  
Author(s):  
David R. Amici ◽  
Jasen M. Jackson ◽  
Kyle A. Metz ◽  
Daniel J. Ansel ◽  
Roger S. Smith ◽  
...  
Keyword(s):  
Stress Response ◽  
Biological Networks ◽  
Genotoxic Stress ◽  
Cellular Stress Response ◽  
Genetic Screens ◽  
Master Regulators ◽  
Functional Relationships ◽  
Response Network ◽  
The Face ◽  
Genome Scale

SummaryThe interrelated programs essential for cellular fitness in the face of stress are critical to understanding tumorigenesis, neurodegeneration, and aging. However, modelling the combinatorial landscape of stresses experienced by diseased cells is challenging, leaving functional relationships within the global stress response network incompletely understood. Here, we leverage genome-scale fitness screening data from 625 cancer cell lines, each representing a unique biological context, to build a network of “coessential” gene relationships centered around master regulators of the response to proteotoxic, oxidative, hypoxic, and genotoxic stress. This approach organizes the stress response into functional modules, identifies genes connecting distinct modules, and reveals mechanisms underlying cellular dependence on individual modules. As an example of the power of this approach, we discover that the previously unannotated HAPSTR (C16orf72) promotes resilience to diverse stressors as a stress-inducible regulator of the E3 ligase HUWE1. Altogether, we present a broadly applicable framework and interactive tool (http://fireworks.mendillolab.org/) to interrogate biological networks using unbiased genetic screens.

scholarly journals Shape selection and mis-assembly in viral capsid formation by elastic frustration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Carlos I Mendoza ◽  
David Reguera
Keyword(s):  
Self Assembly ◽  
Viral Infections ◽  
Coarse Grained ◽  
Energetic Cost ◽  
Mechanical Resistance ◽  
Elastic Stresses ◽  
Shape Selection ◽  
Spherical Structures ◽  
Coarse Grained Simulations ◽  
Successful Replication

The successful assembly of a closed protein shell (or capsid) is a key step in the replication of viruses and in the production of artificial viral cages for bio/nanotechnological applications. During self-assembly, the favorable binding energy competes with the energetic cost of the growing edge and the elastic stresses generated due to the curvature of the capsid. As a result, incomplete structures such as open caps, cylindrical or ribbon-shaped shells may emerge, preventing the successful replication of viruses. Using elasticity theory and coarse-grained simulations, we analyze the conditions required for these processes to occur and their significance for empty virus self-assembly. We find that the outcome of the assembly can be recast into a universal phase diagram showing that viruses with high mechanical resistance cannot be self-assembled directly as spherical structures. The results of our study justify the need of a maturation step and suggest promising routes to hinder viral infections by inducing mis-assembly.

scholarly journals Delineating the early transcriptional specification of the mammalian trachea and esophagus

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Akela Kuwahara ◽  
Ace E Lewis ◽  
Coohleen Coombes ◽  
Fang-Shiuan Leung ◽  
Michelle Percharde ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Mouse Embryos ◽  
Transcriptional Program ◽  
Chip Sequencing ◽  
Fate Specification ◽  
Master Regulators ◽  
Genome Wide ◽  
Single Cell Rna Sequencing ◽  
Genome Scale ◽  
New Framework

The genome-scale transcriptional programs that specify the mammalian trachea and esophagus are unknown. Though NKX2-1 and SOX2 are hypothesized to be co-repressive master regulators of tracheoesophageal fates, this is untested at a whole transcriptomic scale and their downstream networks remain unidentified. By combining single-cell RNA-sequencing with bulk RNA-sequencing of Nkx2-1 mutants and NKX2-1 ChIP-sequencing in mouse embryos, we delineate the NKX2-1 transcriptional program in tracheoesophageal specification, and discover that the majority of the tracheal and esophageal transcriptome is NKX2-1 independent. To decouple the NKX2-1 transcriptional program from regulation by SOX2, we interrogate the expression of newly-identified tracheal and esophageal markers in Sox2/Nkx2-1 compound mutants. Finally, we discover that NKX2-1 binds directly to Shh and Wnt7b and regulates their expression to control mesenchymal specification to cartilage and smooth muscle, coupling epithelial identity with mesenchymal specification. These findings create a new framework for understanding early tracheoesophageal fate specification at the genome-wide level.

scholarly journals Genome-Scale Analysis of the Uses of the Escherichia coli Genome: Model-Driven Analysis of Heterogeneous Data Sets

2003 ◽  
Vol 185 (21) ◽  
pp. 6392-6399 ◽  
Author(s):  
Timothy E. Allen ◽  
Markus J. Herrgård ◽  
Mingzhu Liu ◽  
Yu Qiu ◽  
Jeremy D. Glasner ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protein Synthesis ◽  
In Silico ◽  
Half Life ◽  
Data Sets ◽  
Expression Data ◽  
E Coli ◽  
Model Driven ◽  
Life Data ◽  
Genome Scale

ABSTRACT The recent availability of heterogeneous high-throughput data types has increased the need for scalable in silico methods with which to integrate data related to the processes of regulation, protein synthesis, and metabolism. A sequence-based framework for modeling transcription and translation in prokaryotes has been established and has been extended to study the expression state of the entire Escherichia coli genome. The resulting in silico analysis of the expression state highlighted three facets of gene expression in E. coli: (i) the metabolic resources required for genome expression and protein synthesis were found to be relatively invariant under the conditions tested; (ii) effective promoter strengths were estimated at the genome scale by using global mRNA abundance and half-life data, revealing genes subject to regulation under the experimental conditions tested; and (iii) large-scale genome location-dependent expression patterns with approximately 600-kb periodicity were detected in the E. coli genome based on the 49 expression data sets analyzed. These results support the notion that a structured model-driven analysis of expression data yields additional information that can be subjected to commonly used statistical analyses. The integration of heterogeneous genome-scale data (i.e., sequence, expression data, and mRNA half-life data) is readily achieved in the context of an in silico model.

scholarly journals Competing stress-dependent oligomerization pathways regulate self-assembly of the periplasmic protease-chaperone DegP

2021 ◽  
Vol 118 (32) ◽  
pp. e2109732118
Author(s):  
Robert W. Harkness ◽  
Yuki Toyama ◽  
Zev A. Ripstein ◽  
Huaying Zhao ◽  
Alexander I. M. Sever ◽  
...  
Keyword(s):  
Self Assembly ◽  
Lipid Membranes ◽  
Gram Negative Bacteria ◽  
Protein Homeostasis ◽  
Physiological Conditions ◽  
Assembly Mechanism ◽  
Oligomeric Protein ◽  
Stress Dependent ◽  
Substrate Proteins ◽  
Shed Light

DegP is an oligomeric protein with dual protease and chaperone activity that regulates protein homeostasis and virulence factor trafficking in the periplasm of gram-negative bacteria. A number of oligomeric architectures adopted by DegP are thought to facilitate its function. For example, DegP can form a “resting” hexamer when not engaged to substrates, mitigating undesired proteolysis of cellular proteins. When bound to substrate proteins or lipid membranes, DegP has been shown to populate a variety of cage- or bowl-like oligomeric states that have increased proteolytic activity. Though a number of DegP’s substrate-engaged structures have been robustly characterized, detailed mechanistic information underpinning its remarkable oligomeric plasticity and the corresponding interplay between these dynamics and biological function has remained elusive. Here, we have used a combination of hydrodynamics and NMR spectroscopy methodologies in combination with cryogenic electron microscopy to shed light on the apo-DegP self-assembly mechanism. We find that, in the absence of bound substrates, DegP populates an ensemble of oligomeric states, mediated by self-assembly of trimers, that are distinct from those observed in the presence of substrate. The oligomeric distribution is sensitive to solution ionic strength and temperature and is shifted toward larger oligomeric assemblies under physiological conditions. Substrate proteins may guide DegP toward canonical cage-like structures by binding to these preorganized oligomers, leading to changes in conformation. The properties of DegP self-assembly identified here suggest that apo-DegP can rapidly shift its oligomeric distribution in order to respond to a variety of biological insults.

scholarly journals Self-Assembling Peptides and Their Application in the Treatment of Diseases

2019 ◽  
Vol 20 (23) ◽  
pp. 5850 ◽  
Author(s):  
Lee ◽  
Trinh ◽  
Yoo ◽  
Shin ◽  
Lee ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Controlled Release ◽  
Side Effects ◽  
Tissue Regeneration ◽  
Environmental Conditions ◽  
Self Assembly ◽  
Basic Structure ◽  
Physicochemical Characteristics ◽  
Self Assembling ◽  
Structural Divergence

Self-assembling peptides are biomedical materials with unique structures that are formed in response to various environmental conditions. Governed by their physicochemical characteristics, the peptides can form a variety of structures with greater reactivity than conventional non-biological materials. The structural divergence of self-assembling peptides allows for various functional possibilities; when assembled, they can be used as scaffolds for cell and tissue regeneration, and vehicles for drug delivery, conferring controlled release, stability, and targeting, and avoiding side effects of drugs. These peptides can also be used as drugs themselves. In this review, we describe the basic structure and characteristics of self-assembling peptides and the various factors that affect the formation of peptide-based structures. We also summarize the applications of self-assembling peptides in the treatment of various diseases, including cancer. Furthermore, the in-cell self-assembly of peptides, termed reverse self-assembly, is discussed as a novel paradigm for self-assembling peptide-based nanovehicles and nanomedicines.

scholarly journals Quantitative Analysis of the Phase Transition Mechanism Underpinning the Systemic Self-Assembly of a Mechanopharmaceutical Device

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 15
Author(s):  
Steven Dunne ◽  
Andrew R. Willmer ◽  
Rosemary Swanson ◽  
Deepak Almeida ◽  
Nicole C. Ammerman ◽  
...  
Keyword(s):  
Phase Transition ◽  
Self Assembly ◽  
Half Life ◽  
Drug Loading ◽  
Model Organism ◽  
Compartment Model ◽  
Multiple Dosing ◽  
Transition Mechanism ◽  
Long Term Treatment ◽  
Context Dependent

Clofazimine (CFZ) is a poorly soluble, weakly basic, small molecule antibiotic clinically used to treat leprosy and is now in clinical trials as a treatment for multidrug resistant tuberculosis and COVID-19. CFZ exhibits complex, context-dependent pharmacokinetics that are characterized by an increasing half-life in long term treatment regimens. The systemic pharmacokinetics of CFZ have been previously represented by a nonlinear, 2-compartment model incorporating an expanding volume of distribution. This expansion reflects the soluble-to-insoluble phase transition that the drug undergoes as it precipitates out and accumulates within macrophages disseminated throughout the organism. Using mice as a model organism, we studied the mechanistic underpinnings of this increasing half-life and how the systemic pharmacokinetics of CFZ are altered with continued dosing. To this end, M. tuberculosis infection status and multiple dosing schemes were studied alongside a parameter sensitivity analysis (PSA) to further understanding of systemic drug distribution. Parameter values governing the sigmoidal expansion function that captures the phase transition were methodically varied, and in turn, the systemic concentrations of the drug were calculated and compared to the experimentally measured concentrations of drug in serum and spleen. The resulting amounts of drug sequestered were dependent on the total mass of CFZ administered and the duration of drug loading. This phenomenon can be captured by altering three different parameters of an expansion function corresponding to key biological determinants responsible for the precipitation and the accumulation of the insoluble drug mass in macrophages. Through this analysis of the context dependent pharmacokinetics of CFZ, a predictive framework for projecting the systemic distribution and self-assembly of precipitated drug complexes as intracellular mechanopharmaceutical devices of this and other drugs exhibiting similarly complex pharmacokinetics can be constructed.

scholarly journals A conserved mechanism for meiotic chromosome organization through self-assembly of a filamentous chromosome axis core

2018 ◽  
Author(s):  
Alan M.V. West ◽  
Scott C. Rosenberg ◽  
Sarah N. Ur ◽  
Madison K. Lehmer ◽  
Qiaozhen Ye ◽  
...  
Keyword(s):  
Self Assembly ◽  
Meiotic Chromosome ◽  
Coiled Coil ◽  
Chromosome Organization ◽  
Molecular Architecture ◽  
Master Regulators ◽  
Dna Loop ◽  
Core Proteins ◽  
Protein Components ◽  
Chromosome Axis

AbstractThe meiotic chromosome axis plays key roles in meiotic chromosome organization and recombination, yet the underlying protein components of this structure are highly diverged. Here, we show that “axis core proteins” from budding yeast (Red1), mammals (SYCP2/SYCP3), and plants (ASY3/ASY4) are evolutionarily related and play equivalent roles in chromosome axis assembly. We first identify motifs in each complex that recruit meiotic HORMADs, the master regulators of meiotic recombination. We next find that axis core complexes form homotetrameric (Red1) or heterotetrameric (SYCP2:SYCP3 and ASY3:ASY4) coiled-coil assemblies that further oligomerize into micron-length filaments. Thus, the meiotic chromosome axis core in fungi, mammals, and plants shares a common molecular architecture and role in axis assembly and recombination control. We propose that the meiotic chromosome axis self-assembles through cooperative interactions between dynamic DNA loop-extruding cohesin complexes and the filamentous axis core, then serves as a platform for chromosome organization, recombination, and synaptonemal complex assembly.

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