UNTANGLING THE FOLDING AND FUNCTION OF LEPTIN

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dc.contributor.advisorHaglund, Ellinor
dc.contributor.authorSimien, Jennifer Michelle
dc.contributor.departmentChemistry
dc.date.accessioned2024-07-02T23:42:53Z
dc.date.available2024-07-02T23:42:53Z
dc.date.issued2024
dc.description.degreePh.D.
dc.identifier.urihttps://hdl.handle.net/10125/108415
dc.subjectBiochemistry
dc.subjectBiophysics
dc.subjectLeptin
dc.subjectPierced Lasso Topology
dc.subjectProtein Folding
dc.titleUNTANGLING THE FOLDING AND FUNCTION OF LEPTIN
dc.typeThesis
dcterms.abstractProtein biological function is finely tuned by specific three-dimensional structures where biophysical characteristics drive intermolecular interactions. The fundamental principles encoding structure and function in the amino acid sequence is not yet understood. The discovery of protein entanglements has emerged as a topological complexity that adds ruggedness to the folding free energy landscape by introducing a threading event. Pierced Lasso Topology (PLT) proteins consist of a covalent intramolecular loop that is threaded through by a free terminus of the polypeptide chain. How entangled proteins fold into their active native structures and their roles in biology are unanswered phenomena of nature. The model PLT leptin regulates energy expenditure, cellular proliferation, and immune response upon binding to the cognate leptin receptor (LEP-R). Although the structure of the extracellular complex has been solved, the series of events driving formation of the leptin signaling complex has not yet been elucidated. This dissertation investigates the introduction of PLTs in nature, the leptin folding and threading landscape, and structural elements integral for biological activity. I found that PLTs are conserved in protein superfamilies indicating there is a biological advantage to their complexity. Leptin folding experiments suggest threading is a reversible event in a relatively flat folding landscape and revealed a previously overlooked leptin region is essential for function. These findings are foundational in uncovering the biophysical properties driving self-assembly of protein entanglements essential for human health.
dcterms.extent96 pages
dcterms.languageen
dcterms.publisherUniversity of Hawai'i at Manoa
dcterms.rightsAll UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
dcterms.typeText
local.identifier.alturihttp://dissertations.umi.com/hawii:12055

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