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Title: The molecular basis for ER tubule formation
Author: Brady, Jacob Peter
ISNI:       0000 0004 5362 7237
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Integral membrane proteins of the DP1 and reticulon families are responsible for maintaining the high membrane curvature required for both smooth ER tubules and the edges of ER sheets. Mutations in these proteins lead to motor neurone diseases such as hereditary spastic paraplegia. Reticulon/DP1 proteins contain Reticulon Homology Domains (RHD) that have unusually long (≈30 aa) hydrophobic segments and are proposed to adopt intramembrane helical hairpins that stabilise membrane curvature. I have uncovered the secondary structure and dynamics of the DP1 protein Yop1p and identified a C-terminal conserved amphipathic helix that on its own interacts strongly with negatively charged membranes and is necessary for membrane tubule formation. Analyses of DP1 and reticulon family members indicate that most, if not all, contain C-terminal sequences capable of forming amphipathic helices. Together, these results indicate that amphipathic helices play a previously unrecognised role in RHD membrane curvature stabilisation. This work paves the way towards full structure determination of Yop1p by solution state NMR and marks the first high structural resolution study on an RHD protein.
Supervisor: Schnell, Jason R. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Molecular biophysics (biochemistry) ; Endoplasmic reticulum ; Yop1p ; amphipathic helix ; reticulon ; tubular ER ; nuclear magnetic resonance ; membrane proteins