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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 ?-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 ?-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.

SUBMITTER: Malmos KG

PROVIDER: S-EPMC4974396 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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How Glycosaminoglycans Promote Fibrillation of Salmon Calcitonin.

Malmos Kirsten Gade KG Bjerring Morten M Jessen Christian Moestrup CM Nielsen Erik Holm Toustrup EH Poulsen Ebbe T ET Christiansen Gunna G Vosegaard Thomas T Skrydstrup Troels T Enghild Jan J JJ Pedersen Jan Skov JS Otzen Daniel E DE

The Journal of biological chemistry 20160608 32

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 ...[more]

PMID: 27281819

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Project description:Kamihira2000 - calcitonin fibrillation kinetics This model studies the kinetics of human calcitonin fibrillation described as a two-step process. Empirical data is used to determine the parameter values. Results show that the first step in fibrillation is a slow homogenous reaction and the second step is a fast autocatalytic heterogenous reaction. This model is described in the article: Conformational transitions and fibrillation mechanism of human calcitonin as studied by high-resolution solid-state 13C NMR. Kamihira M, Naito A, Tuzi S, Nosaka AY, Saitô H. Protein Sci. 2000 May; 9(5): 867-877 Abstract: Conformational transitions of human calcitonin (hCT) during fibril formation in the acidic and neutral conditions were investigated by high-resolution solid-state 13C NMR spectroscopy. In aqueous acetic acid solution (pH 3.3), a local alpha-helical form is present around Gly10 whereas a random coil form is dominant as viewed from Phe22, Ala26, and Ala31 in the monomer form on the basis of the 13C chemical shifts. On the other hand, a local beta-sheet form as viewed from Gly10 and Phe22, and both beta-sheet and random coil as viewed from Ala26 and Ala31 were detected in the fibril at pH 3.3. The results indicate that conformational transitions from alpha-helix to beta-sheet, and from random coil to beta-sheet forms occurred in the central and C-terminus regions, respectively, during the fibril formation. The increased 13C resonance intensities of fibrils after a certain delay time suggests that the fibrillation can be explained by a two-step reaction mechanism in which the first step is a homogeneous association to form a nucleus, and the second step is an autocatalytic heterogeneous fibrillation. In contrast to the fibril at pH 3.3, the fibril at pH 7.5 formed a local beta-sheet conformation at the central region and exhibited a random coil at the C-terminus region. Not only a hydrophobic interaction among the amphiphilic alpha-helices, but also an electrostatic interaction between charged side chains can play an important role for the fibril formation at pH 7.5 and 3.3 acting as electrostatically favorable and unfavorable interactions, respectively. These results suggest that hCT fibrils are formed by stacking antiparallel beta-sheets at pH 7.5 and a mixture of antiparallel and parallel beta-sheets at pH 3.3. This model is hosted on BioModels Database and identified by: BIOMD0000000614. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

How Glycosaminoglycans Promote Fibrillation of Salmon Calcitonin.

Publications

How Glycosaminoglycans Promote Fibrillation of Salmon Calcitonin.

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