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Biophysical investigation of membrane curvature sensing amphipathic helices
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Brooks, Rhiannon (2021) Biophysical investigation of membrane curvature sensing amphipathic helices. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3766466
Abstract
The curvature of biological membranes in cells and organelles is an important aspect of membrane morphology, and has been linked to a diverse range of biochemical processes such as membrane trafficking and apoptosis. Whilst the lipid composition can influence the spontaneous curvature a membrane adopts, curvature largely depends on the behaviour of specific proteins that can generate and sense this curvature. A variety of mechanisms for how proteins achieve this have been proposed, which includes the insertion of amphipathic helices (APHs); amino acid sequences arranged in such a way that the resulting helix has discrete hydrophobic and polar faces allowing them to partition into one leaflet of a bilayer. However, these are notoriously difficult to identify as considerable differences in the sequences, physical properties and chemistry has been observed in those that have been discovered, hindering the identification of a general mechanism for how these motifs associate with membranes. Recently, RTNLB13, an integral membrane protein of the reticulon (RTN) family, was shown to contain an APH that is necessary for the proteins function in shaping highly-curved tubules in the endoplasmic reticulum (ER). Yet, its precise role in curvature generation remains ambiguous.
Herein, the curvature-dependence of this APH for folding and binding to a library of model membranes is demonstrated using several biophysical techniques, suggesting its predominant behaviour follows a curvature sensing mechanism. This operates by the insertion of a shallow hydrophobic face into lipid packing defects, a direct consequence of introducing curvature to a membrane, which provides additional stabilisation to the curved structure of the ER tubules. This APH has been speculated to be conserved across all RTN family members so experimental evidence for the existence of curvature sensing APHs in other RTN isoforms is also presented. Finally, the APHs characterised in this work inform the design of novel peptides with the potential to sense membrane curvature for applications in drug delivery or diagnostics, which are then biophysically characterised to show a dependence on curvature for folding and membrane-binding.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QH Natural history Q Science > QP Physiology |
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Library of Congress Subject Headings (LCSH): | Cell membranes, Membrane lipids, Endoplasmic reticulum, Biophysics, Curvature, Amphiphiles, Membrane proteins -- Physiological transport | ||||
Official Date: | September 2021 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Molecular Analytical Science Centre for Doctoral Training | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Dixon, Ann M. ; Smith, Corinne J. | ||||
Sponsors: | Engineering and Physical Sciences Research Council | ||||
Format of File: | |||||
Extent: | xvi, 188 leaves : illustrations | ||||
Language: | eng |
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