Journal
FEBS LETTERS
Volume 596, Issue 22, Pages 2928-2939Publisher
WILEY
DOI: 10.1002/1873-3468.14455
Keywords
acidic pH; amyloid fibrillation; functional amyloids; heparin interaction; intrinsically disordered proteins; parathyroid hormone
Funding
- German Science Foundation (DFG) [391498659, RTG 2467, 189853844, CRC TRR 102]
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In acidic secretory granules of mammalian cells, peptide hormones may be stored as functional amyloid fibrils, and polyanion heparin can promote the fibril formation of PTH.
In acidic secretory granules of mammalian cells, peptide hormones including the parathyroid hormone are presumably stored in the form of functional amyloid fibrils. Mature PTH, however, is considerably positively charged in acidic environments, a condition known to impede unassisted self-aggregation into fibrils. Here, we studied the role of the polyanion heparin on promoting fibril formation of PTH. Employing ITC, CD spectroscopy, NMR, SAXS, and fluorescence-based assays, we could demonstrate that heparin binds PTH with submicromolar affinity and facilitates its conversion into fibrillar seeds, enabling rapid formation of amyloid fibrils under acidic conditions. In the absence of heparin, PTH remained in a soluble monomeric state. We suspect that heparin-like surfaces are required in vivo to convert PTH efficiently into fibrillar deposits.
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