Show simple item record

dc.contributor.authorCiaccio, Natalie Anne
dc.contributor.authorReynolds, T. Steele
dc.contributor.authorMiddaugh, C. Russell
dc.contributor.authorLaurence, Jennifer S.
dc.date.accessioned2017-05-09T20:05:48Z
dc.date.available2017-05-09T20:05:48Z
dc.date.issued2012-11-05
dc.identifier.citationCiaccio, N. A., Reynolds, T. S., Middaugh, C. R., & Laurence, J. S. (2012). Influence of the Valine Zipper Region on the Structure and Aggregation of the Basic Leucine Zipper (bZIP) Domain of Activating Transcription Factor 5 (ATF5). Molecular Pharmaceutics, 9(11), 3190–3199. http://doi.org/10.1021/mp300288nen_US
dc.identifier.urihttp://hdl.handle.net/1808/24055
dc.description.abstractProtein aggregation is a major problem for biopharmaceuticals. While the control of aggregation is critically important for the future of protein pharmaceuticals, mechanisms of aggregate assembly, particularly the role that structure plays, are still poorly understood. Increasing evidence indicates that partially folded intermediates critically influence the aggregation pathway. We have previously reported the use of the basic leucine zipper (bZIP) domain of Activating Transcription Factor 5 (ATF5) as a partially folded model system to investigate protein aggregation. This domain contains three regions with differing structural propensity: a N-terminal polybasic region, a central helical leucine zipper region, and a C-terminal extended valine zipper region. Additionally, a centrally positioned cysteine residue readily forms an intermolecular disulfide bond that reduces aggregation. Computational analysis of ATF5 predicts that the valine zipper region facilitates self-association. Here we test this hypothesis using a truncated mutant lacking the C-terminal valine zipper region. We compare the structure and aggregation of this mutant to the wild-type (WT) form under both reducing and non-reducing conditions. Our data indicate that removal of this region results in a loss of alpha-helical structure in the leucine zipper and a change in the mechanism of self-association. The mutant form displays increased association at low temperature but improved resistance to thermally induced aggregation.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/mp300288n.en_US
dc.subjectATF5en_US
dc.subjectATFxen_US
dc.subjectbZIPen_US
dc.subjectZipperen_US
dc.subjectHelixen_US
dc.subjectAggregationen_US
dc.subjectStabilityen_US
dc.titleInfluence of the Valine Zipper Region on the Structure and Aggregation of the Basic Leucine Zipper (bZIP) Domain of Activating Transcription Factor 5 (ATF5)en_US
dc.typeArticleen_US
kusw.kuauthorCiaccio, Natalie A.
kusw.kuauthorReynolds, T. Steele
kusw.kuauthorMiddaugh, C. Russell
kusw.kuauthorLaurence, Jennifer S.
kusw.kudepartmentPharmaceutical Chemistryen_US
dc.identifier.doi10.1021/mp300288nen_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC3535187en_US
dc.rights.accessrightsopenAccess


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record