title: Structural characterization of amyloid fibrils from the human parathyroid hormone.
abstract: Amyloid deposits are common in various tissues as a consequence of misfolded proteins. However, secretory protein and peptides are often stored in membrane coated granules as functional amyloids. In this article, we present a detailed characterization of in vitro generated amyloid fibrils from human parathyroid hormone (hPTH(1-84)). Fully mature fibrils could be obtained after a short lag phase within less than one hour at 65°C. These fibrils showed all characteristic of a cross-β structure. Protease cleavage combined with mass spectrometry identified the central region of the peptide hormone involved in the fibril core formation. EGCG, an inhibitor of amyloid fibril formation, showed binding to residues in the peptide monomers corresponding to the later fibril core and thus explaining the inhibition of the fibril growth. Conformational and dynamic studies by solid-state NMR further corroborated the cross-β core of the fibrils, but also identified highly mobile segments with a random coil structure not belonging to the rigid fibril core.
authors.affiliation: Institut für Physik, Biophysik, Martin-Luther-Universität Halle-Wittenberg, D-06120 Halle, Germany; Mitteldeutsches Zentrum für Struktur und Dynamik der Proteine (MZP), Martin-Luther-Universität Halle-Wittenberg, D-06120 Halle, Germany.
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Gopalswamy
authors.affiliation: Institut für Physik, Biophysik, Martin-Luther-Universität Halle-Wittenberg, D-06120 Halle, Germany; Mitteldeutsches Zentrum für Struktur und Dynamik der Proteine (MZP), Martin-Luther-Universität Halle-Wittenberg, D-06120 Halle, Germany.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Institut für Medizinische Physik und Biophysik, Universität Leipzig, D-04107 Leipzig, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Adler
authors.affiliation: Institut für Physik, Biophysik, Martin-Luther-Universität Halle-Wittenberg, D-06120 Halle, Germany; Mitteldeutsches Zentrum für Struktur und Dynamik der Proteine (MZP), Martin-Luther-Universität Halle-Wittenberg, D-06120 Halle, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Institut für Physik, Biophysik, Martin-Luther-Universität Halle-Wittenberg, D-06120 Halle, Germany; Mitteldeutsches Zentrum für Struktur und Dynamik der Proteine (MZP), Martin-Luther-Universität Halle-Wittenberg, D-06120 Halle, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Henze
authors.affiliation: Institut für Pharmazeutische Biotechnologie, Universität Ulm, D-89081 Ulm, Germany.
authors.forename: Senthil T
authors.initials: ST
authors.lastname: Kumar
authors.affiliation: Institut für Pharmazeutische Biotechnologie, Universität Ulm, D-89081 Ulm, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fändrich
authors.affiliation: Institut für Medizinische Physik und Biophysik, Universität Leipzig, D-04107 Leipzig, Germany.
authors.forename: Holger A
authors.initials: HA
authors.lastname: Scheidt
authors.affiliation: Institut für Medizinische Physik und Biophysik, Universität Leipzig, D-04107 Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Huster
authors.affiliation: Institut für Physik, Biophysik, Martin-Luther-Universität Halle-Wittenberg, D-06120 Halle, Germany; Mitteldeutsches Zentrum für Struktur und Dynamik der Proteine (MZP), Martin-Luther-Universität Halle-Wittenberg, D-06120 Halle, Germany. Electronic address: jochen.balbach@physik.uni-halle.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Balbach
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010281:Parathyroid Hormone / Q000737:chemistry* / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D066329:Protein Aggregates; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: D000682:Amyloid; C470125:PTH protein, human; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D066329:Protein Aggregates
keywords: Amyloid fibrils; EGCG; Electron microscopy; Human parathyroid hormone; MALDI-TOF mass spectrometry; NMR spectroscopy