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Full-Text Articles in Life Sciences

Multiscale Simulations Of Intrinsically Disordered Proteins, Xiaorong Liu Jul 2019

Multiscale Simulations Of Intrinsically Disordered Proteins, Xiaorong Liu

Doctoral Dissertations

Intrinsically disordered proteins (IDPs) lack stable secondary and/or tertiary structures under physiological conditions. The have now been recognized to play important roles in numerous biological processes, particularly cellular signaling and regulation. Mutation of IDPs are frequently associated with human diseases, such as cancers and neuron degenerative diseases. Therefore, it is important to understand the structure, dynamics, and interactions of IDPs, so as to establish the mechanistic basis of how intrinsic disorder mediates versatile functions and how such mechanisms may fail in human diseases. However, the heterogeneous structural ensembles of IDPs are not amenable to high resolution characterization solely through ...


Identifying Functional Components Of The Endoplasmic Reticulum Quality Control And Degradation Factor Edem1, Lydia Lamriben Nov 2018

Identifying Functional Components Of The Endoplasmic Reticulum Quality Control And Degradation Factor Edem1, Lydia Lamriben

Doctoral Dissertations

The ER Degradation-Enhancing Mannosidase-Like protein 1 (EDEM1) is a critical endoplasmic reticulum (ER) quality control factor involved in identifying and directing non-native proteins to the ER-associated protein degradation (ERAD) pathway. However, its recognition and binding properties have remained enigmatic since its discovery. Here we provide evidence for an additional redox-sensitive interaction between EDEM1 and Z/NHK that requires the presence of the single Cys on the α-1 antitrypsin ERAD clients. Moreover, this Cys-dependent interaction is necessary when the proteins are isolated under stringent detergent conditions, ones in which only strong covalent interactions can be sustained. This interaction is inherent to ...


Investigating The Impact Of Small Molecule Ligands And The Proteostasis Network On Protein Folding Inside The Cell, Karan Hingorani Nov 2016

Investigating The Impact Of Small Molecule Ligands And The Proteostasis Network On Protein Folding Inside The Cell, Karan Hingorani

Doctoral Dissertations

The folded forms of most proteins are critical to their functions. Despite the complexity of the cellular milieu and the presence of high-risk deleterious interactions, there is a high level of fidelity observed in the folding process for entire proteomes. Two important reasons for this are the presence of the quality control machinery consisting of chaperones and degradation enzymes that work jointly to optimize the population of the folded state and interaction partners that re-enforce the functional state and add to the competitive advantage of an organism. While substantial effort has been directed to understand protein folding and interactions in ...


Exploring The Impact Of The E. Coli Proteostasis Network On The Folding Fate Of Proteins With Different Intrinsic Biophysical Properties, Kristine Faye R. Pobre Mar 2016

Exploring The Impact Of The E. Coli Proteostasis Network On The Folding Fate Of Proteins With Different Intrinsic Biophysical Properties, Kristine Faye R. Pobre

Doctoral Dissertations

The three-dimensional (3D) native structure of most proteins is crucial for their functions. Despite the complex cellular environment and the variety of challenges that proteins experience as they fold, proteins can still fold to their native states with high fidelity. The reason for this is the presence of the cellular proteostasis network (PN), consisting of molecular chaperones and degradation enzymes, that collaborates to maintain proteostasis, in which the necessary levels of functional proteins are optimized. Although extensive research has been carried out on the mechanisms of individual components of the proteostasis network, little is known about how these components contribute ...


The Unavoidable Threat Of Aggregation: Implications For Folding And Function Of A Β-Rich Protein, Mylene Hazelle Anne Ferrolino May 2013

The Unavoidable Threat Of Aggregation: Implications For Folding And Function Of A Β-Rich Protein, Mylene Hazelle Anne Ferrolino

Open Access Dissertations

Protein aggregation has been implicated in several catastrophic diseases (neurodegeneration, diabetes, ALS) and its complexity has also become a major obstacle in large-scale production of protein-based therapeutics. Despite the generic behavior of proteins to aggregate, only a few globular proteins have known aggregation mechanisms. At present, there have been no clear connections between a protein folding, function and aggregation. We have tackled the challenge of understanding the links between a protein's natural tendency to fold and function with its propensity to misfold and aggregate. Using a predominantly beta-sheet protein whose in vitro folding has been explored in detail: cellular ...


Components Of A Protein Machine: Allosteric Domain Assembly And A Disordered C-Terminus Enable The Chaperone Functions Of Hsp70, Robert G. Smock Sep 2011

Components Of A Protein Machine: Allosteric Domain Assembly And A Disordered C-Terminus Enable The Chaperone Functions Of Hsp70, Robert G. Smock

Open Access Dissertations

Hsp70 molecular chaperones protect proteins from aggregation, assist in their native structure formation, and regulate stress responses in the cell. A mechanistic understanding of Hsp70 function will be necessary to explain its physiological roles and guide the therapeutic modulation of various disease states. To this end, several fundamental features of the Hsp70 structure-function relationship are investigated. The central component of Hsp70 chaperone function is its capacity for allosteric signaling between structural domains and tunable binding of misfolded protein substrates. In order to identify a cooperative network of sites that mediates interdomain allostery within Hsp70, a mutational correlation analysis is performed ...