Structural dynamics associated with intermediate formation in an archetypal conformational disease
Nyon, Mun Peak and Segu, Lakshmi and Cabrita, L.D. and Lévy, Géraldine R. and Kirkpatrick, J. and Roussel, B.D. and Patschull, Anathe O.M. and Barrett, Tracey E. and Ekeowa, U.I. and Kerr, R. and Waudby, Christopher A. and Kalsheker, N. and Hill, M. and Thalassinos, Konstantinos and Lomas, D.A. and Christodoulou, John and Gooptu, Bibek (2012) Structural dynamics associated with intermediate formation in an archetypal conformational disease. Structure 20 (3), pp. 504-512. ISSN 0969-2126.
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 α1-antitrypsin (Lys154Asn) that forms polymers recapitulating the conformer-specific neo-epitope observed in polymers that form in vivo. Lys154Asn α1-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.
|School:||Birkbeck Schools and Departments > School of Science > Biological Sciences|
|Research Centre:||Structural Molecular Biology, Institute of (ISMB)|
|Date Deposited:||07 Mar 2012 14:57|
|Last Modified:||06 Dec 2016 10:40|
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