Effects of local factors on proline isomerization: NMR analysis of proline-driven conformational exchange in the Itk SH2 domain

dc.contributor.author Mayo, Melissa
dc.contributor.department Biochemistry, Biophysics and Molecular Biology
dc.date 2020-11-09T01:20:57.000
dc.date.accessioned 2021-02-26T08:57:51Z
dc.date.available 2021-02-26T08:57:51Z
dc.date.copyright Thu Jan 01 00:00:00 UTC 2004
dc.date.issued 2004-01-01
dc.description.abstract <p>In cellular signaling cascades, protein activity can be controlled by molecular-switch directed ligand recognition. With differential ligand-binding arising from interconversion of two prolyl imide bond conformers, peptidyl-prolyl cis/trans isomerization has been identified as a noncovalent molecular switch mechanism. Involved in the T cell signaling pathway, Interleukin-2 tyrosine kinase (Itk) contains a Src homology 2 (SH2) regulatory domain that exists in solution as two conformers due to prolyl isomerization within the native state protein. To investigate the role that local structural factors play in governing and enabling prolyl-driven conformational heterogeneity within the Itk SH2 domain, variants from alanine-scanning mutagenesis and peptide models of the proline-containing loop were characterized using NMR spectroscopy. The data indicate that several factors play a role, including a stabilizing hydrophobic patch within the loop, the identity of the residues directly preceding the isomeric proline, and strain introduced at the base of the loop. Local factors alone did not account for the large degree of conformational heterogeneity observed, indicating that interactions within the folded protein also play an important role in enabling dual imide bond occupancy. As understanding of the molecular level determinants increases with continued structural characterizations, the mechanisms underlying molecular switches will be illuminated.</p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/rtd/20750/
dc.identifier.articleid 21749
dc.identifier.contextkey 20115208
dc.identifier.doi https://doi.org/10.31274/rtd-20201107-307
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath rtd/20750
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/98117
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/rtd/20750/Mayo_ISU_2004_M39.pdf|||Fri Jan 14 22:28:02 UTC 2022
dc.subject.keywords Biochemistry, biophysics, and molecular biology
dc.subject.keywords Biochemistry
dc.title Effects of local factors on proline isomerization: NMR analysis of proline-driven conformational exchange in the Itk SH2 domain
dc.type article
dc.type.genre thesis
dspace.entity.type Publication
relation.isOrgUnitOfPublication faf0a6cb-16ca-421c-8f48-9fbbd7bc3747
thesis.degree.discipline Biochemistry
thesis.degree.level thesis
thesis.degree.name Master of Science
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