Early stages of amyloid fibril formation studied by liquid-state NMR

the peptide hormone glucagon

Anna Sigrid Pii Svane, Kasper Jahn, Taru Deva, Anders Malmendal, Daniel Otzen, Jens Dittmer, Niels Chr Nielsen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

The 29-residue peptide hormone glucagon forms amyloid fibrils within a few hours at low pH. In this study, we use glucagon as a model system to investigate fibril formation by liquid-state (1)H-NMR spectroscopy One-dimensional, correlation, and diffusion experiments monitoring the fibril formation process provide insight into the early stages of the pathway on which the molecules aggregate to fibrils. In conjunction with these techniques, exchange experiments give information about the end-state conformation. Within the limits of detection, there are no signs of larger oligomeric intermediates in the course of the fibril formation process. Kinetic information is extracted from the time course of the residual free glucagon signal decay. This suggests that glucagon amyloids form by a nucleated growth mechanism in which trimers (rather than monomers) of glucagon interact directly with the growing fibrils rather than with each other. The results of proton/deuterium exchange experiments on mature fibrils with subsequent dissolution show that the N-terminal of glucagon is the least amenable to exchange, which indicates that this part is strongly involved in the intermolecular bonds of the fibrils.
OriginalsprogEngelsk
TidsskriftBiophysical Journal
Vol/bind95
Udgave nummer1
Sider (fra-til)366-77
Antal sider12
ISSN0006-3495
DOI
StatusUdgivet - 1 jul. 2008
Udgivet eksterntJa

Citer dette

Svane, Anna Sigrid Pii ; Jahn, Kasper ; Deva, Taru ; Malmendal, Anders ; Otzen, Daniel ; Dittmer, Jens ; Nielsen, Niels Chr. / Early stages of amyloid fibril formation studied by liquid-state NMR : the peptide hormone glucagon. I: Biophysical Journal. 2008 ; Bind 95, Nr. 1. s. 366-77.
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abstract = "The 29-residue peptide hormone glucagon forms amyloid fibrils within a few hours at low pH. In this study, we use glucagon as a model system to investigate fibril formation by liquid-state (1)H-NMR spectroscopy One-dimensional, correlation, and diffusion experiments monitoring the fibril formation process provide insight into the early stages of the pathway on which the molecules aggregate to fibrils. In conjunction with these techniques, exchange experiments give information about the end-state conformation. Within the limits of detection, there are no signs of larger oligomeric intermediates in the course of the fibril formation process. Kinetic information is extracted from the time course of the residual free glucagon signal decay. This suggests that glucagon amyloids form by a nucleated growth mechanism in which trimers (rather than monomers) of glucagon interact directly with the growing fibrils rather than with each other. The results of proton/deuterium exchange experiments on mature fibrils with subsequent dissolution show that the N-terminal of glucagon is the least amenable to exchange, which indicates that this part is strongly involved in the intermolecular bonds of the fibrils.",
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Early stages of amyloid fibril formation studied by liquid-state NMR : the peptide hormone glucagon. / Svane, Anna Sigrid Pii; Jahn, Kasper; Deva, Taru; Malmendal, Anders; Otzen, Daniel; Dittmer, Jens; Nielsen, Niels Chr.

I: Biophysical Journal, Bind 95, Nr. 1, 01.07.2008, s. 366-77.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Early stages of amyloid fibril formation studied by liquid-state NMR

T2 - the peptide hormone glucagon

AU - Svane, Anna Sigrid Pii

AU - Jahn, Kasper

AU - Deva, Taru

AU - Malmendal, Anders

AU - Otzen, Daniel

AU - Dittmer, Jens

AU - Nielsen, Niels Chr

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N2 - The 29-residue peptide hormone glucagon forms amyloid fibrils within a few hours at low pH. In this study, we use glucagon as a model system to investigate fibril formation by liquid-state (1)H-NMR spectroscopy One-dimensional, correlation, and diffusion experiments monitoring the fibril formation process provide insight into the early stages of the pathway on which the molecules aggregate to fibrils. In conjunction with these techniques, exchange experiments give information about the end-state conformation. Within the limits of detection, there are no signs of larger oligomeric intermediates in the course of the fibril formation process. Kinetic information is extracted from the time course of the residual free glucagon signal decay. This suggests that glucagon amyloids form by a nucleated growth mechanism in which trimers (rather than monomers) of glucagon interact directly with the growing fibrils rather than with each other. The results of proton/deuterium exchange experiments on mature fibrils with subsequent dissolution show that the N-terminal of glucagon is the least amenable to exchange, which indicates that this part is strongly involved in the intermolecular bonds of the fibrils.

AB - The 29-residue peptide hormone glucagon forms amyloid fibrils within a few hours at low pH. In this study, we use glucagon as a model system to investigate fibril formation by liquid-state (1)H-NMR spectroscopy One-dimensional, correlation, and diffusion experiments monitoring the fibril formation process provide insight into the early stages of the pathway on which the molecules aggregate to fibrils. In conjunction with these techniques, exchange experiments give information about the end-state conformation. Within the limits of detection, there are no signs of larger oligomeric intermediates in the course of the fibril formation process. Kinetic information is extracted from the time course of the residual free glucagon signal decay. This suggests that glucagon amyloids form by a nucleated growth mechanism in which trimers (rather than monomers) of glucagon interact directly with the growing fibrils rather than with each other. The results of proton/deuterium exchange experiments on mature fibrils with subsequent dissolution show that the N-terminal of glucagon is the least amenable to exchange, which indicates that this part is strongly involved in the intermolecular bonds of the fibrils.

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