scholarly journals Identification of Two Early Folding Stage Prion Non-Local Contacts Suggested to Serve as Key Steps in Directing the Final Fold to Be Either Native or Pathogenic

2021 ◽  
Vol 22 (16) ◽  
pp. 8619
Author(s):  
Fernando Bergasa-Caceres ◽  
Herschel A. Rabitz
Keyword(s):  
Prion Protein ◽  
Molten Globule ◽  
Folding Pathway ◽  
Initiation Point ◽  
Local Contact ◽  
Collapse Model ◽  
Non Local ◽  
Key Steps ◽  
Potential Initiation

The initial steps of the folding pathway of the C-terminal domain of the murine prion protein mPrP(90–231) are predicted based on the sequential collapse model (SCM). A non-local dominant contact is found to form between the connecting region between helix 1 and b-sheet 1 and the C-terminal region of helix 3. This non-local contact nucleates the most populated molten globule-like intermediate along the folding pathway. A less stable early non-local contact between segments 120–124 and 179–183, located in the middle of helix 2, promotes the formation of a less populated molten globule-like intermediate. The formation of the dominant non-local contact constitutes an example of the postulated Nature’s Shortcut to the prion protein collapse into the native structure. The possible role of the less populated molten globule-like intermediate is explored as the potential initiation point for the folding for three pathogenic mutants (T182A, I214V, and Q211P in mouse prion numbering) of the prion protein.

Models of cooperativity in protein folding

1995 ◽  
Vol 348 (1323) ◽  
pp. 61-70 ◽  
Keyword(s):  
Protein Folding ◽  
Molten Globule ◽  
Core Collapse ◽  
Hydrophobic Core ◽  
Model Studies ◽  
Helix Formation ◽  
Collapse Model ◽  
Folding Pathways ◽  
State Behaviour ◽  
Denatured States

What is the basis for the two-state cooperativity of protein folding? Since the 1950s, three main models have been put forward. 1. In ‘helix-coil’ theory, cooperativity is due to local interactions among near neighbours in the sequence. Helix-coil cooperativity is probably not the principal basis for the folding of globular proteins because it is not two-state, the forces are weak, it does not account for sheet proteins, and there is no evidence that helix formation precedes the formation of a hydrophobic core in the folding pathways. 2. In the ‘sidechain packing’ model, cooperativity is attributed to the jigsaw-puzzle-like complementary fits of sidechains. This too is probably not the basis of folding cooperativity because exact models and experiments on homopolymers with sidechains give no evidence that sidechain freezing is two-state, sidechain complementarities in proteins are only weak trends, and the molten globule model predicted by this model is far more native-like than experiments indicate. 3. In the ‘hydrophobic core collapse’ model, cooperativity is due to the assembly of non-polar residues into a good core. Exact model studies show that this model gives two-state behaviour for some sequences of hydrophobic and polar monomers. It is based on strong forces. There is considerable experimental evidence for the kinetics this model predicts: the development of hydrophobic clusters and cores is concurrent with secondary structure formation. It predicts compact denatured states with sizes and degrees of disorder that are in reasonable agreement with experiments.

Phonological Complexity: Bernese Swiss German in Ohio and Misiones

2021 ◽  
Vol 18 (2) ◽  
pp. 1-26
Author(s):  
Robert Klosinski ◽  
Andrew D. Hoffman
Keyword(s):  
United States ◽  
Language Change ◽  
The United States ◽  
Heritage Languages ◽  
Swiss German ◽  
Local Contact ◽  
Additional Reference ◽  
Phonological Complexity

Abstract This article investigates the notion of complexity as it applies to two phonological characteristics of Heritage Bernese Swiss German, namely /l/-vocalization and /nd/-velarization. We survey literature on the role of complexity in language change generally, as well as how it applies to heritage languages specifically. We then present findings from our study of two groups of Heritage Bernese speakers, one in the United States and one in Argentina, with additional reference to the local contact languages. Our findings suggest that the loss of /nd/-velarization in Misiones, Argentina is most likely the result of an internally-driven reduction of complexity. For both the Ohio and Misiones communities, however, /l/-vocalization has been maintained. We conclude by discussing the importance of research into language dyads beyond those in the United States as well as pursuing research on lesser-studied heritage languages.

On velocity gradient dynamics and turbulent structure

2015 ◽  
Vol 780 ◽  
pp. 60-98 ◽  
Author(s):  
J. M. Lawson ◽  
J. R. Dawson
Keyword(s):  
Velocity Gradient ◽  
Local Strain ◽  
Turbulent Structure ◽  
Stochastic Estimation ◽  
Spatially Resolved ◽  
Gradient Dynamics ◽  
Layer Structures ◽  
Non Local ◽  
Conditional Averaging

The statistics of the velocity gradient tensor $\unicode[STIX]{x1D63C}=\boldsymbol{{\rm\nabla}}\boldsymbol{u}$, which embody the fine scales of turbulence, are influenced by turbulent ‘structure’. Whilst velocity gradient statistics and dynamics have been well characterised, the connection between structure and dynamics has largely focused on rotation-dominated flow and relied upon data from numerical simulation alone. Using numerical and spatially resolved experimental datasets of homogeneous turbulence, the role of structure is examined for all local (incompressible) flow topologies characterisable by $\unicode[STIX]{x1D63C}$. Structures are studied through the footprints they leave in conditional averages of the $Q=-\text{Tr}(\unicode[STIX]{x1D63C}^{2})/2$ field, pertinent to non-local strain production, obtained using two complementary conditional averaging techniques. The first, stochastic estimation, approximates the $Q$ field conditioned upon $\unicode[STIX]{x1D63C}$ and educes quantitatively similar structure in both datasets, dissimilar to that of random Gaussian velocity fields. Moreover, it strongly resembles a promising model for velocity gradient dynamics recently proposed by Wilczek & Meneveau (J. Fluid Mech., vol. 756, 2014, pp. 191–225), but is derived under a less restrictive premise, with explicitly determined closure coefficients. The second technique examines true conditional averages of the $Q$ field, which is used to validate the stochastic estimation and provide insights towards the model’s refinement. Jointly, these approaches confirm that vortex tubes are the predominant feature of rotation-dominated regions and additionally show that shear layer structures are active in strain-dominated regions. In both cases, kinematic features of these structures explain alignment statistics of the pressure Hessian eigenvectors and why local and non-local strain production act in opposition to each other.

scholarly journals Synthesis runs counter to directional folding of a nascent protein domain

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiuqi Chen ◽  
Nandakumar Rajasekaran ◽  
Kaixian Liu ◽  
Christian M. Kaiser
Keyword(s):  
Single Molecule ◽  
Molten Globule ◽  
Elongation Factor ◽  
Protein Domain ◽  
Folding Pathway ◽  
Native Structure ◽  
Folding Intermediates ◽  
C Terminus

Abstract Folding of individual domains in large proteins during translation helps to avoid otherwise prevalent inter-domain misfolding. How folding intermediates observed in vitro for the majority of proteins relate to co-translational folding remains unclear. Combining in vivo and single-molecule experiments, we followed the co-translational folding of the G-domain, encompassing the first 293 amino acids of elongation factor G. Surprisingly, the domain remains unfolded until it is fully synthesized, without collapsing into molten globule-like states or forming stable intermediates. Upon fully emerging from the ribosome, the G-domain transitions to its stable native structure via folding intermediates. Our results suggest a strictly sequential folding pathway initiating from the C-terminus. Folding and synthesis thus proceed in opposite directions. The folding mechanism is likely imposed by the final structure and might have evolved to ensure efficient, timely folding of a highly abundant and essential protein.

scholarly journals The Role of Cellular Prion Protein in Cancer Biology: A Potential Therapeutic Target

2021 ◽  
Vol 11 ◽  
Author(s):  
Manqiu Ding ◽  
Yongqiang Chen ◽  
Yue Lang ◽  
Li Cui
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Cell Survival ◽  
Cancer Cells ◽  
Prion Protein ◽  
Therapeutic Target ◽  
Cancer Biology ◽  
Cellular Prion Protein ◽  
Potential Therapeutic Target

Prion protein has two isoforms including cellular prion protein (PrPC) and scrapie prion protein (PrPSc). PrPSc is the pathological aggregated form of prion protein and it plays an important role in neurodegenerative diseases. PrPC is a glycosylphosphatidylinositol (GPI)-anchored protein that can attach to a membrane. Its expression begins at embryogenesis and reaches the highest level in adulthood. PrPC is expressed in the neurons of the nervous system as well as other peripheral organs. Studies in recent years have disclosed the involvement of PrPC in various aspects of cancer biology. In this review, we provide an overview of the current understanding of the roles of PrPC in proliferation, cell survival, invasion/metastasis, and stem cells of cancer cells, as well as its role as a potential therapeutic target.

scholarly journals Synthesis runs counter to directional folding of a nascent protein domain

2020 ◽  
Author(s):  
Xiuqi Chen ◽  
Nandakumar Rajasekaran ◽  
Kaixian Liu ◽  
Christian M. Kaiser
Keyword(s):  
Single Molecule ◽  
Molten Globule ◽  
Elongation Factor ◽  
Protein Domain ◽  
Folding Pathway ◽  
Native Structure ◽  
Folding Intermediates ◽  
C Terminus

AbstractFolding of individual domains in large proteins during translation helps to avoid otherwise prevalent inter-domain misfolding. How folding intermediates observed in vitro for the majority of proteins relate to co-translational folding remains unclear. Combining in vivo and single-molecule experiments, we followed the co-translational folding of the G-domain, encompassing the first 293 amino acids of elongation factor G. Surprisingly, the domain remains unfolded until it is fully synthesized, without collapsing into molten globule-like states or forming stable intermediates. Upon fully emerging from the ribosome, the G-domain transitions to its stable native structure via folding intermediates. Our results suggest a strictly sequential folding pathway initiating from the C-terminus. Folding and synthesis thus proceed in opposite directions. The folding mechanism is likely imposed by the final structure and might have evolved to ensure efficient, timely folding of a highly abundant and essential protein.

scholarly journals Setting up the stage for smart sustainable city: international and ukrainian context. The role of smart solutions

2020 ◽  
pp. 13-24
Author(s):  
Anna Pozdniakova ◽  
Iryna Velska
Keyword(s):  
Smart City ◽  
Smart Cities ◽  
Knowledge Generation ◽  
Sustainable City ◽  
The World ◽  
Key Steps ◽  
Human Component

The paper analyzes the key steps taken by different cities worldwide and gathered into a clear step-by-step roadmap that can be useful for emerging smart cities. The Roadmap covers three main stages as we see them during the process of development: preparation, formation and spreading stages. We reveal how this is incorporated in the Ukrainian context. Our analysis of smart city solutions from all over the world (based on the BeeSmartCity database) showed that the tech component on its own is not enough to overcome urban challenges within different domains (environment, economy, government etc.), as we see each of the solutions has a human component involved in a form of knowledge generation and sharing, different forms of co-creation and partnership etc. Thus, ICTs are a required but not a sufficient element of building successful citizen-friendly and resilient cities.

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