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Structural dynamics associated with intermediate formation in an archetypal conformational disease

Nyon, MP; Segu, L; Cabrita, LD; Lévy, GR; Kirkpatrick, J; Roussel, BD; Patschull, AO; ... Gooptu, B; + view all (2012) Structural dynamics associated with intermediate formation in an archetypal conformational disease. Structure , 20 (3) pp. 504-512. 10.1016/j.str.2012.01.012. Green open access

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Abstract

In conformational diseases, native protein conformers convert to pathological intermediates that polymerize. Structural characterization of these key intermediates is challenging. They are unstable and minimally populated in dynamic equilibria that may be perturbed by many analytical techniques. We have characterized a forme fruste deficiency variant of α(1)-antitrypsin (Lys154Asn) that forms polymers recapitulating the conformer-specific neo-epitope observed in polymers that form in vivo. Lys154Asn α(1)-antitrypsin populates an intermediate ensemble along the polymerization pathway at physiological temperatures. Nuclear magnetic resonance spectroscopy was used to report the structural and dynamic changes associated with this. Our data highlight an interaction network likely to regulate conformational change and do not support the recent contention that the disease-relevant intermediate is substantially unfolded. Conformational disease intermediates may best be defined using powerful but minimally perturbing techniques, mild disease mutants, and physiological conditions.

Type: Article
Title: Structural dynamics associated with intermediate formation in an archetypal conformational disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.str.2012.01.012
Publisher version: http://dx.doi.org/10.1016/j.str.2012.01.012
Language: English
Additional information: Copyright © 2012 Elsevier Ltd. Open access under the CC BY license (http://creativecommons.org/licenses/by/3.0/).
Keywords: Epitopes, Humans, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Polymerization, Protein Conformation, Proteostasis Deficiencies, alpha 1-Antitrypsin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > VP: Health
URI: https://discovery.ucl.ac.uk/id/eprint/1344968
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