How Glycosaminoglycans Promote Fibrillation of Salmon Calcitonin

Kirsten G Malmos; Morten Bjerring; Christian Moestrup Jessen; Erik Holm Toustrup Nielsen; Ebbe Toftgaard Poulsen; Gunna Christiansen; Thomas Vosegaard; Troels Skrydstrup; Jan J Enghild; Jan Skov Pedersen; Daniel E Otzen

doi:10.1074/jbc.M116.715466

How Glycosaminoglycans Promote Fibrillation of Salmon Calcitonin

Kirsten G Malmos, Morten Bjerring, Christian Moestrup Jessen, Erik Holm Toustrup Nielsen, Ebbe Toftgaard Poulsen, Gunna Christiansen, Thomas Vosegaard, Troels Skrydstrup, Jan J Enghild, Jan Skov Pedersen, Daniel E Otzen

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

16 Citationer (Scopus)

Abstract

Glycosaminoglycans (GAGs) bind all known amyloid plaques and help store protein hormones in (acidic) granular vesicles, but the molecular mechanisms underlying these important effects are unclear. Here we investigate GAG interactions with the peptide hormone salmon calcitonin (sCT). GAGs induce fast sCT fibrillation at acidic pH and only bind monomeric sCT at acidic pH, inducing sCT helicity. Increasing GAG sulfation expands the pH range for binding. Heparin, the most highly sulfated GAG, binds sCT in the pH interval 3-7. Small angle x-ray scattering indicates that sCT monomers densely decorate and pack single heparin chains, possibly via hydrophobic patches on helical sCT. sCT fibrillates without GAGs, but heparin binding accelerates the process by decreasing the otherwise long fibrillation lag times at low pH and accelerates fibril growth rates at neutral pH. sCT·heparin complexes form β-sheet-rich heparin-covered fibrils. Solid-state NMR reveals that heparin does not alter the sCT fibrillary core around Lys ¹¹ but makes changes to Val ⁸ on the exterior side of the β-strand, possibly through contacts to Lys ¹⁸. Thus GAGs significantly modulate sCT fibrillation in a pH-dependent manner by interacting with both monomeric and aggregated sCT.

Originalsprog	Engelsk
Tidsskrift	Journal of Biological Chemistry
Vol/bind	291
Nummer	32
Sider (fra-til)	16849-16862
Antal sider	31
ISSN	0021-9258
DOI	https://doi.org/10.1074/jbc.M116.715466
Status	Udgivet - 5 aug. 2016

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title = "How Glycosaminoglycans Promote Fibrillation of Salmon Calcitonin",

abstract = "Glycosaminoglycans (GAGs) bind all known amyloid plaques and help store protein hormones in (acidic) granular vesicles, but the molecular mechanisms underlying these important effects are unclear. Here we investigate GAG interactions with the peptide hormone salmon calcitonin (sCT). GAGs induce fast sCT fibrillation at acidic pH and only bind monomeric sCT at acidic pH, inducing sCT helicity. Increasing GAG sulfation expands the pH range for binding. Heparin, the most highly sulfated GAG, binds sCT in the pH interval 3-7. Small angle x-ray scattering indicates that sCT monomers densely decorate and pack single heparin chains, possibly via hydrophobic patches on helical sCT. sCT fibrillates without GAGs, but heparin binding accelerates the process by decreasing the otherwise long fibrillation lag times at low pH and accelerates fibril growth rates at neutral pH. sCT·heparin complexes form β-sheet-rich heparin-covered fibrils. Solid-state NMR reveals that heparin does not alter the sCT fibrillary core around Lys 11 but makes changes to Val 8 on the exterior side of the β-strand, possibly through contacts to Lys 18. Thus GAGs significantly modulate sCT fibrillation in a pH-dependent manner by interacting with both monomeric and aggregated sCT.",

author = "Malmos, {Kirsten G} and Morten Bjerring and Jessen, {Christian Moestrup} and Nielsen, {Erik Holm Toustrup} and Poulsen, {Ebbe Toftgaard} and Gunna Christiansen and Thomas Vosegaard and Troels Skrydstrup and Enghild, {Jan J} and Pedersen, {Jan Skov} and Otzen, {Daniel E}",

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AU - Malmos, Kirsten G

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AU - Nielsen, Erik Holm Toustrup

AU - Poulsen, Ebbe Toftgaard

AU - Christiansen, Gunna

AU - Vosegaard, Thomas

AU - Skrydstrup, Troels

AU - Enghild, Jan J

AU - Pedersen, Jan Skov

AU - Otzen, Daniel E

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AB - Glycosaminoglycans (GAGs) bind all known amyloid plaques and help store protein hormones in (acidic) granular vesicles, but the molecular mechanisms underlying these important effects are unclear. Here we investigate GAG interactions with the peptide hormone salmon calcitonin (sCT). GAGs induce fast sCT fibrillation at acidic pH and only bind monomeric sCT at acidic pH, inducing sCT helicity. Increasing GAG sulfation expands the pH range for binding. Heparin, the most highly sulfated GAG, binds sCT in the pH interval 3-7. Small angle x-ray scattering indicates that sCT monomers densely decorate and pack single heparin chains, possibly via hydrophobic patches on helical sCT. sCT fibrillates without GAGs, but heparin binding accelerates the process by decreasing the otherwise long fibrillation lag times at low pH and accelerates fibril growth rates at neutral pH. sCT·heparin complexes form β-sheet-rich heparin-covered fibrils. Solid-state NMR reveals that heparin does not alter the sCT fibrillary core around Lys 11 but makes changes to Val 8 on the exterior side of the β-strand, possibly through contacts to Lys 18. Thus GAGs significantly modulate sCT fibrillation in a pH-dependent manner by interacting with both monomeric and aggregated sCT.

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How Glycosaminoglycans Promote Fibrillation of Salmon Calcitonin

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