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Please use this identifier to cite or link to this item: http://arks.princeton.edu/ark:/88435/dsp01cn69m739r
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dc.contributor.advisorYan, Nieng
dc.contributor.authorWu, Xuelan
dc.contributor.otherChemistry Department
dc.date.accessioned2023-07-06T20:26:18Z-
dc.date.available2023-12-14T13:00:07Z-
dc.date.created2023-01-01
dc.date.issued2023
dc.identifier.urihttp://arks.princeton.edu/ark:/88435/dsp01cn69m739r-
dc.description.abstractMembrane transporter proteins play critical roles in understanding biological processes, disease mechanisms, and drug development. One unique type of membrane transporter is sterol transporters, which differ from general models due to their substrates’ insolubility in aqueous environments and affinity to lipids. Despite posing challenges in studies due to its hydrophobic nature, cholesterol plays a critical role in many biological processes, including being an essential component of mammalian cell membranes, a precursor for bile acid and hormone syntheses and a vital signaling molecule for developmental pathways. Elevated cholesterol levels are associated with cardiovascular diseases, Alzheimer’s disease, cancers, and other metabolic disorders. In the past century, studies on the regulation of cholesterol homeostasis through cholesterol transporters has not only benefited human health, but also led to the discovery of a number of fundamental cellular processes, signaling pathways, and molecular mechanisms. Niemann-Pick disease, type C (NPC) is a neurodegenerative disease caused by defects in genes encoding lysosomal cholesterol transporters NPC1 and NPC2. The two proteins work collaboratively to govern the cellular intake of exogenous cholesterol, and they serve as an exemplary case for sterol transporter studies. The soluble single-domain protein NPC2 binds cholesterol from the intraluminal vesicles, protects the hydrophobic molecule from the hydrophilic lumen, and transports it to the site of NPC1, a lysosomal membrane protein. Mechanistic studies of the NPC proteins have been critical to understanding the disease-associated mutations and potential therapeutics that can restore impaired functions. With the interdisciplinary studies presented in this thesis, the application of electron cryo-microscopy combined with chemical biology techniques has greatly advanced the understanding of the structures and functions of NPC proteins, shedding light on the major stages of NPC-mediated cholesterol transport.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherPrinceton, NJ : Princeton University
dc.subjectcholesterol transport
dc.subjectlysosomal storage
dc.subjectmembrane protein
dc.subjectNiemann-Pick disease type C
dc.subjectsingle-particle cryo-EM
dc.subjectstructural dynamics
dc.subject.classificationChemistry
dc.subject.classificationBiochemistry
dc.subject.classificationBiophysics
dc.titleSTRUCTURAL AND DYNAMIC CHARACTERIZATION OF LYSOSOMAL CHOLESTEROL TRANSPORTERS
dc.typeAcademic dissertations (Ph.D.)
pu.embargo.terms2023-12-14
pu.date.classyear2023
pu.departmentChemistry
Appears in Collections:Chemistry

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