Structural dynamics associated with intermediate formation in an archetypal conformational disease.
Structure
; 20(3): 504-12, 2012 Mar 07.
Article
en En
| MEDLINE
| ID: mdl-22405009
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Conformación Proteica
/
Modelos Moleculares
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Alfa 1-Antitripsina
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Deficiencias en la Proteostasis
/
Epítopos
Tipo de estudio:
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Structure
Asunto de la revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
BIOTECNOLOGIA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Reino Unido