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dc.contributor.authorCiaccio, Natalie Anne
dc.contributor.authorLaurence, Jennifer S.
dc.date.accessioned2017-05-08T18:53:20Z
dc.date.available2017-05-08T18:53:20Z
dc.date.issued2009
dc.identifier.citationCiaccio, N. A., & Laurence, J. S. (2009). Effects of Disulfide Bond Formation and Protein Helicity on the Aggregation of Activating Transcription Factor 5 (ATF5). Molecular Pharmaceutics, 6(4), 1205–1215. http://doi.org/10.1021/mp900058ten_US
dc.identifier.urihttp://hdl.handle.net/1808/24023
dc.description.abstractAmorphous aggregation is a major problem for protein biopharmaceuticals, and aggregate formation in a drug formulation can have serious health implications for the patient. In many cases, an immunogenic response is generated from the administration of a drug product containing aggregated protein. This becomes especially significant when the patient requires long-term or repeated administration of the drug, because the likelihood of a severe immune response increases. While the prevention of protein aggregation is critically important for the future of protein pharmaceuticals, the process is still poorly understood. The lack of understanding regarding non-fibrillar aggregation is largely due to the fact that assembly is difficult to study. In particular the role that various structural features (i.e. α-helix, β-structure, disulfide bonds) play in the aggregation process varies with the amino acid sequence and is dependent upon tertiary structure and solution conditions. Well-structured proteins do not readily aggregate in solution, whereas partially unfolded proteins tend to aggregate rapidly and often become insoluble. Here, we present a unique and simple system for studying amorphous protein aggregation. We have previously reported the isolation of the basic leucine zipper (bZIP) domain of activating transcription factor 5 (ATF5), a protein notable for its potential as a pharmaceutical target for treatment of glioblastoma multiforme. This domain consists of a single α-helix and possesses a single cysteine residue. It is only partially structured and displays marginal stability in solution under physiological conditions. We have modulated solution conditions that affect backbone solubility and the oxidation state of the thiol to successfully investigate the role that α-helical structure and disulfide bond formation play in protein stability. Our data indicate that covalent cross-linking helps to retain ATF5’s helicity, which inhibits the formation of large aggregates. These studies have led to the identification of stabilizing conditions for ATF5, which will enable further study of the protein as a pharmaceutical target. Moreover, this work has general implications for analyzing stability of helical proteins in vitro and the specific atomic-level interactions in ATF5 that contribute to instability and self-association.en_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/mp900185u.en_US
dc.subjectATF5en_US
dc.subjectATFxen_US
dc.subjectbZIPen_US
dc.subjectDisulfide bonden_US
dc.subjectHelixen_US
dc.subjectAggregationen_US
dc.subjectStabilityen_US
dc.titleEffects of Dusulfide Bond Formation and Protein Helicity on the Aggregation of Activating Transcription Factor 5 (ATF5)en_US
dc.typeArticleen_US
kusw.kuauthorCiaccio, Natalie A.
kusw.kuauthorLaurence, Jennifer S.
kusw.kudepartmentPharmaceutical Chemistryen_US
dc.identifier.doi10.1021/mp900058ten_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC3414431en_US
dc.rights.accessrightsopenAccess


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