Membrane contact site targeting and functions of Vps13 and related bridging lipid transporters
department or school: Medicine, Faculty of
department or school: Medical Genetics, Department of
data provider: DSpace
degree campus: UBCV
creator: Dziurdzik, Samantha Katarzyna
issued: 2024-09-30T07:00:00Z
issued: 2023
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Specialized proteins facilitate inter-organelle lipid transfer at membrane contact sites (MCSs), regions where organelles are tethered in close proximity. The VPS13 proteins constitute a unique class of lipid transporters that simultaneously bridge organelles at MCSs and channel phospholipids between them. Of importance, mutations in each of the four human VPS13 (VPS13A-D) genes are associated with distinct neurological disorders, and it is thought that loss of lipid transport at specific MCSs underlies the cause of these diverse diseases. Understanding how VPS13 proteins target membranes and how their MCS recruitment is regulated is therefore crucial for developing a better understanding of the underlying disease pathologies. Here, we uncover a conserved VPS13 membrane targeting mechanism using the Saccharomyces cerevisiae model that has a single Vps13 which localizes to multiple organelles and contact sites. We identify a shared motif in the three known organelle-specific adaptors that recruit Vps13, and establish the necessity of these motifs for interaction. We find all adaptors interact at an uncharacterized six-repeat domain that we named the Vps13 Adaptor Binding (VAB) domain. We demonstrate VAB domain repeats 5–6 are sufficient for adaptor interaction and recruitment supporting a model where adaptors compete for binding to a single pocket. Importantly, modeling a spastic ataxia VPS13D missense mutation in this pocket blocks adaptor interactions, Vps13 recruitment, and further results in a vacuolar protein secretion defect that is not associated with any of the known adaptors. These findings support a conserved adaptor binding role for the VAB domain and suggest the presence of as-yet unidentified adaptors in both yeast and humans. Our studies further identify Fmp27/Hob1 and Ypr117w/Hob2 as putative Vps13 structural homologs localized at endoplasmic reticulum (ER)-plasma membrane (PM) contacts. Recruitment of ER-anchored Fmp27 to PM contacts similarly relies …
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/85489
note: MEMBRANE CONTACT SITE TARGETING AND FUNCTIONS OF VPS13 AND RELATED BRIDGING LIPID TRANSPORTERS by Samantha Katarzyna Dziurdzik B.Sc., The University of Waterloo, 2017 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2023 © Samantha Katarzyna Dziurdzik, 2023 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Membrane contact site targeting and functions of Vps13 and related bridging lipid transporters submitted by Samantha Katarzyna Dziurdzik in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Medical Genetics Examining Committee: Elizabeth Conibear, Professor, Medical Genetics, UBC Supervisor Peter Stirling, Associate Professor, Medical Genetics, UBC Supervisory Committee Member Calvin Yip, Associate Professor, Biochemistry and Molecular Biology, UBC University Examiner Robert Molday, Professor, Biochemistry and Molecular Biology, UBC University Examiner Additional Supervisory Committee Members: I. Robert Nabi, Professor, Cellular and Physiological Sciences, UBC Supervisory Committee Member Christopher Loewen, Professor, Cellular and Physiological Sciences, UBC Supervisory Committee Member iii Abstract Specialized proteins facilitate inter-organelle lipid transfer at membrane contact sites (MCSs), regions where organelles are tethered in close proximity. The VPS13 proteins constitute a unique class of lipid transporters that simultaneously bridge organelles at MCSs and channel phospholipids between them. Of importance, mutations in each of the four human VPS13 (VPS13A-D) genes are associated with distinct neurological disorders, and it is thought that loss of lipid transport at specific MCSs underlies the cause of these diverse diseases. Understan…
has type: Thesis/Dissertation
date issued: 2023-11
is shown at: 10.14288/1.0435199
language: eng
degree discipline: Medical Genetics
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Conibear, Elizabeth
type: Text
identifier URI: http://hdl.handle.net/2429/85489