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Toward a molecular mechanism of phase separation in disordered elastin-like proteins

Author: Yue Zhang; Mississippi State University,; Mississippi State University. Department of Chemistry,
Publisher: Mississippi State : Mississippi State University, 2017.
Dissertation: Thesis (Ph. D.) Mississippi State University. Department of Chemistry 2017
Edition/Format:   Thesis/dissertation : Document : Thesis/dissertation : eBook   Computer File : English
Summary:
Since the last decade, an increasing number of proteins have been shown to be capable of undergoing reversible liquid-liquid phase separation (LLPS) in response to an external stimulus, and the resulting protein-rich phase (coacervate) is considered as one of the main components of membrane-less organelles. Most of these proteins are intrinsically disordered proteins (IDPs) or contain intrinsically disordered  Read more...
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Details

Genre/Form: Academic theses
Material Type: Document, Thesis/dissertation, Internet resource
Document Type: Internet Resource, Computer File
All Authors / Contributors: Yue Zhang; Mississippi State University,; Mississippi State University. Department of Chemistry,
OCLC Number: 1018944581
Notes: Title from PDF title page (viewed on May 31, 2018).
Description: 1 online resource (xi, 137 pages) : illustrations (some color), charts (some color)
Details: Mode of access: Internet via the World Wide Web.; System requirements: Internet connectivity; World Wide Web browser software; Adobe Acrobat Reader.
Responsibility: by Yue Zhang.
More information:

Abstract:

Since the last decade, an increasing number of proteins have been shown to be capable of undergoing reversible liquid-liquid phase separation (LLPS) in response to an external stimulus, and the resulting protein-rich phase (coacervate) is considered as one of the main components of membrane-less organelles. Most of these proteins are intrinsically disordered proteins (IDPs) or contain intrinsically disordered regions. More importantly, LLPS often plays an important role in cellular signaling and development of cells and tissues. However, the molecular mechanisms underlying LLPS of proteins remain poorly understood. Elastin-like proteins (ELPs), a class of IDPs derived from the hydrophobic domains of tropoelastin, are known to undergo LLPS reversibly above a concentration-dependent transition temperature (TT), allowing ELPs to be a promising thermo-responsive drug delivery vector for treating cancer. Previous studies have suggested that, as temperature increases, ELPs experience an increased propensity for type II beta-turns. Our hypothesis is that the interaction is initiated at the beta-turn positions. In this work, integrative approaches including experimental and computational methods were employed to study the early stages of ELP phase separation. Using nuclear magnetic resonance spectroscopy (NMR), and paramagnetic relaxation enhancement (PRE), we have characterized structural properties of self-association in several ELPs. NMR chemical shifts suggest that ELPs adopt a beta-turn conformation even at temperatures below the TT. The intermolecular PRE reveals there is a stronger interaction between the higher beta-turn propensity regions. Building on this observation, a series of structural ensembles were generated for ELP incorporating differing amounts of beta-turn bias, from 1% to 90%. To mimic the early stages of the phase change, two monomers were paired, assuming preferential interaction at beta-turn regions. Following dimerization, the ensemble-averaged hydrodynamic properties were calculated for each degree of beta-turn bias, and results were compared with analytical ultracentrifugation (AUC) experiments at various temperatures. The ensemble calculation reveals that accessible surface area changes dramatically as oligomers are formed from monomers with a high beta-turn content. Together, these observations suggest a model where ELP self-association is initiated at beta-turn positions, where the driving force of phase separation is solvent exclusion due to changes in the hydrophobic accessible surface area.

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