Solution conformation and heparin-induced dimerization of the full-length extracellular domain of the human amyloid precursor protein

dc.creatorGralle, M
dc.creatorOliveira, CLP
dc.creatorGuerreiro, LH
dc.creatorMcKinstry, WJ
dc.creatorGalatis, D
dc.creatorMasters, CL
dc.creatorCappai, R
dc.creatorParker, MW
dc.creatorRamos, CHI
dc.creatorTorriani, I
dc.creatorFerreira, ST
dc.date2006
dc.date45352
dc.date2014-11-19T11:15:24Z
dc.date2015-11-26T18:02:43Z
dc.date2014-11-19T11:15:24Z
dc.date2015-11-26T18:02:43Z
dc.date.accessioned2018-03-29T00:44:27Z
dc.date.available2018-03-29T00:44:27Z
dc.identifierJournal Of Molecular Biology. Academic Press Ltd Elsevier Science Ltd, v. 357, n. 2, n. 493, n. 508, 2006.
dc.identifier0022-2836
dc.identifierWOS:000236120200013
dc.identifier10.1016/j.jmb.2005.12.053
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/71841
dc.identifierhttp://www.repositorio.unicamp.br/handle/REPOSIP/71841
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/71841
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1292317
dc.descriptionProteolytic cleavage of the amyloid precursor protein (APP) by beta and gamma-secretases gives rise to the beta-amyloid peptide, considered to be a causal factor in Alzheimer's disease. Conversely, the soluble extracellular domain of APP (sAPP alpha), released upon its cleavage by alpha-secretase, plays a number of important physiological functions. Several APP fragments have been structurally characterized at atomic resolution, but the structures of intact APP and of full-length sAPP alpha have not been determined. Here, ab initio reconstruction of molecular models from high-resolution solution X-ray scattering (SAXS) data for the two main isoforms of sAPP alpha (sAPP alpha(695) and sAPP alpha(770)) provided models of sufficiently high resolution to identify distinct structural domains of APP. The fragments for which structures are known at atomic resolution were fitted within the solution models of full-length sAPPa, allowing localization of important functional sites (i.e. glycosylation, protease inhibitory and heparin-binding sites). Furthermore, combined results from SAXS, analytical ultracentrifugation (AUC) and size-exclusion chromatography (SEC) analysis indicate that both sAPP alpha isoforms are monomeric in solution. On the other hand, SEC, bis-ANS fluorescence, AUC and SAXS measurements showed that sAPPa forms a 2:1 complex with heparin. A conformational model for the sAPP alpha:heparin complex was also derived from the SAXS data. Possible implications of such complex formation for the physiological dimerization of APP and biological signaling are discussed in terms of the structural models proposed. (c) 2005 Elsevier Ltd. All rights reserved.
dc.description357
dc.description2
dc.description493
dc.description508
dc.languageen
dc.publisherAcademic Press Ltd Elsevier Science Ltd
dc.publisherLondon
dc.publisherInglaterra
dc.relationJournal Of Molecular Biology
dc.relationJ. Mol. Biol.
dc.rightsfechado
dc.rightshttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.sourceWeb of Science
dc.subjectanalytical ultracentrifugation
dc.subjectmodeling
dc.subjectsignal transduction
dc.subjectsmall-angle X-ray scattering
dc.subjectstructural domains
dc.subjectSolution Scattering Data
dc.subjectRay Solution Scattering
dc.subjectSmall-angle Scattering
dc.subjectAlzheimers-disease
dc.subjectMacromolecular Complexes
dc.subjectCytoplasmic Domain
dc.subjectCrystal-structure
dc.subjectTransgenic Mice
dc.subjectSecreted Forms
dc.subjectCell-surface
dc.titleSolution conformation and heparin-induced dimerization of the full-length extracellular domain of the human amyloid precursor protein
dc.typeArtículos de revistas


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