Structural dynamics associated with intermediate formation in an archetypal conformational disease

M.P. Nyon; L. Segu; L.D. Cabrita; G.R. Lévy; J. Kirkpatrick; B.D. Roussel; A.O.M. Patschull; T.E. Barrett; U.I. Ekeowa; R. Kerr; C. A. Waudby; N. Kalsheker; M. Hill; K. Thalassinos; D.A. Lomas; J. Christodoulou; B Gooptu

doi:10.1016/j.str.2012.01.012

Structural dynamics associated with intermediate formation in an archetypal conformational disease

M.P. Nyon, L. Segu, L.D. Cabrita, G.R. Lévy, J. Kirkpatrick, B.D. Roussel, A.O.M. Patschull, T.E. Barrett, U.I. Ekeowa, R. Kerr, C. A. Waudby, N. Kalsheker, M. Hill, K. Thalassinos, D.A. Lomas, J. Christodoulou, B Gooptu

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

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 - antitrypsin (Lys154Asn) that forms polymers recapitulating the conformer-specific neo-epitope observed in polymers that form in vivo. Lys154Asn α -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.

Original language	English
Pages (from-to)	504-512
Number of pages	9
Journal	Structure
Volume	20
Issue number	3
DOIs	https://doi.org/10.1016/j.str.2012.01.012
Publication status	Published - 7 Mar 2012

Access to Document

10.1016/j.str.2012.01.012

Cite this

Nyon, M. P., Segu, L., Cabrita, L. D., Lévy, G. R., Kirkpatrick, J., Roussel, B. D., Patschull, A. O. M., Barrett, T. E., Ekeowa, U. I., Kerr, R., Waudby, C. A., Kalsheker, N., Hill, M., Thalassinos, K., Lomas, D. A., Christodoulou, J., & Gooptu, B. (2012). Structural dynamics associated with intermediate formation in an archetypal conformational disease. Structure, 20(3), 504-512. https://doi.org/10.1016/j.str.2012.01.012

@article{9e8a2f27759b42b781121509b86b601e,

title = "Structural dynamics associated with intermediate formation in an archetypal conformational disease",

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 - antitrypsin (Lys154Asn) that forms polymers recapitulating the conformer-specific neo-epitope observed in polymers that form in vivo. Lys154Asn α -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.",

author = "M.P. Nyon and L. Segu and L.D. Cabrita and G.R. L{\'e}vy and J. Kirkpatrick and B.D. Roussel and A.O.M. Patschull and T.E. Barrett and U.I. Ekeowa and R. Kerr and Waudby, {C. A.} and N. Kalsheker and M. Hill and K. Thalassinos and D.A. Lomas and J. Christodoulou and B Gooptu",

year = "2012",

month = mar,

day = "7",

doi = "10.1016/j.str.2012.01.012",

language = "English",

volume = "20",

pages = "504--512",

journal = "Structure",

issn = "0969-2126",

publisher = "Cell Press",

number = "3",

}

Nyon, MP, Segu, L, Cabrita, LD, Lévy, GR, Kirkpatrick, J, Roussel, BD, Patschull, AOM, Barrett, TE, Ekeowa, UI, Kerr, R, Waudby, CA, Kalsheker, N, Hill, M, Thalassinos, K, Lomas, DA, Christodoulou, J & Gooptu, B 2012, 'Structural dynamics associated with intermediate formation in an archetypal conformational disease', Structure, vol. 20, no. 3, pp. 504-512. https://doi.org/10.1016/j.str.2012.01.012

TY - JOUR

T1 - Structural dynamics associated with intermediate formation in an archetypal conformational disease

AU - Nyon, M.P.

AU - Segu, L.

AU - Cabrita, L.D.

AU - Lévy, G.R.

AU - Kirkpatrick, J.

AU - Roussel, B.D.

AU - Patschull, A.O.M.

AU - Barrett, T.E.

AU - Ekeowa, U.I.

AU - Kerr, R.

AU - Waudby, C. A.

AU - Kalsheker, N.

AU - Hill, M.

AU - Thalassinos, K.

AU - Lomas, D.A.

AU - Christodoulou, J.

AU - Gooptu, B

PY - 2012/3/7

Y1 - 2012/3/7

N2 - 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 - antitrypsin (Lys154Asn) that forms polymers recapitulating the conformer-specific neo-epitope observed in polymers that form in vivo. Lys154Asn α -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.

AB - 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 - antitrypsin (Lys154Asn) that forms polymers recapitulating the conformer-specific neo-epitope observed in polymers that form in vivo. Lys154Asn α -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.

UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84857926856&md5=833520e08e1baae08b6e72342f0a8403

U2 - 10.1016/j.str.2012.01.012

DO - 10.1016/j.str.2012.01.012

M3 - Article

AN - SCOPUS:84857926856

SN - 0969-2126

VL - 20

SP - 504

EP - 512

JO - Structure

JF - Structure

IS - 3

ER -

Structural dynamics associated with intermediate formation in an archetypal conformational disease

Abstract

Access to Document

Other files and links

Fingerprint

Cite this