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Effects of glycosylation on the structure and fibrillization of prion protein fragments

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dc.contributor.advisor Barbara Imperiali. en_US
dc.contributor.author Bosques, Carlos J. (Carlos Javier), 1974- en_US
dc.contributor.other Massachusetts Institute of Technology. Dept. of Chemistry. en_US
dc.date.accessioned 2006-03-24T18:06:04Z
dc.date.available 2006-03-24T18:06:04Z
dc.date.copyright 2003 en_US
dc.date.issued 2003 en_US
dc.identifier.uri http://hdl.handle.net/1721.1/29953
dc.description Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2003. en_US
dc.description Vita. en_US
dc.description Includes bibliographical references. en_US
dc.description.abstract It is now accepted that the structural transition from PrPc to PrPSc is the major event leading to transmissible spongiform encephalopathies. Although the mechanism of this transition remains elusive, glycosylation has been proposed to impede the PrPc to PrPSc conversion. Structural studies on glycoprotein fragments in the Imperiali group has previously shown that N-linked glycosylation can play a major role modulating polypeptide conformation. It has also been shown that glycosylation can alter the thermodynamics of disulfide bond formation, favoring oxidation. To address the role of glycosylation on PrP, we have prepared glycosylated and unglycosylated peptides derived from the 175-195 fragment of the human prion protein. The synthesis of a Fmoc-Asn[chitobiose(TBDMS)5-OH amino acid precursor allowed the preparation of the glycopeptide in high yields. Comparison of the structure, aggregation kinetics, fibril formation capabilities and redox susceptibility of Cys 179 has shown that the N-linked glycan (at Asn 181) significantly reduces the rate of fibrillization by promoting intermolecular disulfide formation via Cys 179. Furthermore, the aggressive fibrillization of a C179S mutant of this fragment highlights the significant role of disulfide stability in retarding the rate of fibril formation. Additionally, a novel method for the temporal control of fibrillization of this peptide was developed using a synthetic photolabile linker and a "fibril inhibitory unit" positioned at the N-terminus of the peptide. This stabilized the fragment as a soluble monomeric species until photoactivation, which triggered the peptide self-assembly. en_US
dc.description.statementofresponsibility by Carlos J. Bosques. en_US
dc.format.extent 213 leaves en_US
dc.format.extent 6848935 bytes
dc.format.extent 6848741 bytes
dc.format.mimetype application/pdf
dc.format.mimetype application/pdf
dc.language.iso eng en_US
dc.publisher Massachusetts Institute of Technology en_US
dc.rights M.I.T. 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. See provided URL for inquiries about permission. en_US
dc.rights.uri http://dspace.mit.edu/handle/1721.1/7582
dc.subject Chemistry. en_US
dc.title Effects of glycosylation on the structure and fibrillization of prion protein fragments en_US
dc.type Thesis en_US
dc.description.degree Ph.D. en_US
dc.contributor.department Massachusetts Institute of Technology. Dept. of Chemistry. en_US
dc.identifier.oclc 53381954 en_US


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