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J Biol Chem. 2016 Aug 5;291(32):16849-62. doi: 10.1074/jbc.M116.715466. Epub 2016 Jun 8.

How Glycosaminoglycans Promote Fibrillation of Salmon Calcitonin.

Author information

1
From the Interdisciplinary Nanoscience Center (iNANO) and Center for Insoluble Protein Structures (inSPIN), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark, Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
2
From the Interdisciplinary Nanoscience Center (iNANO) and Center for Insoluble Protein Structures (inSPIN), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark, Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000 Aarhus C, Denmark.
3
From the Interdisciplinary Nanoscience Center (iNANO) and Center for Insoluble Protein Structures (inSPIN), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark.
4
Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.
5
Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 4, DK-8000 Aarhus, Denmark, and.
6
From the Interdisciplinary Nanoscience Center (iNANO) and Center for Insoluble Protein Structures (inSPIN), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark, Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark, dao@inano.au.dk.

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.

KEYWORDS:

amyloid; fibril; glycosaminoglycan; heparin; hormone; salmon calcitonin

PMID:
27281819
PMCID:
PMC4974396
DOI:
10.1074/jbc.M116.715466
[Indexed for MEDLINE]
Free PMC Article

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