Nanostructure and stability of calcitonin amyloids

Federica Rigoldi, Pierangelo Metrangolo, Alberto Redaelli, Alfonso Gautieri (Corresponding Author)

    Research output: Contribution to journalArticleScientificpeer-review

    15 Citations (Scopus)


    Calcitonin is a 32-amino acid thyroid hormone that can form amyloid fibrils. The structural basis of the fibril formation and stabilization is still debated and poorly understood. The reason is that NMR data strongly suggest antiparallel β-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp 15 to Phe 19 of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel β-sheets. In this work, we first predict the structure of human calcitonin through two complementary molecular dynamics (MD) methods, finding that human calcitonin forms an α-helix. We use extensive MD simulations to compare previously proposed calcitonin fibril structures. We find that two conformations, the parallel arrangement and one of the possible antiparallel structures (with Asp 15 and Phe 19 aligned), are highly stable and ordered. Nonetheless, fibrils with parallel molecules show bulky loops formed by residues 1 to 7 located on the same side, which could limit or prevent the formation of larger amyloids. We investigate fibrils formed by the DFNKF peptide by simulating different arrangements of this amyloidogenic core sequence. We show that DFNKF fibrils are highly stable when assembled in parallel β-sheets, whereas they quickly unfold in antiparallel conformation. Our results indicate that the DFNKF peptide represents only partially the full-length calcitonin behavior. Contrary to the full-length polypeptide, in fact, the DFNKF sequence is not stable in antiparallel conformation, suggesting that the residue flanking the amyloidogenic peptide contributes to the stabilization of the experimentally observed antiparallel β-sheet packing.
    Original languageEnglish
    Pages (from-to)7348-7357
    JournalJournal of Biological Chemistry
    Issue number18
    Publication statusPublished - 5 Mar 2017
    MoE publication typeA1 Journal article-refereed


    This work was supported by Fondazione Cariplo Grants 2013-0766 and 2016-0481. Supported by European Research Council (ERC) starting grant FOLDHALO 307108.


    • Amyloid/chemistry
    • Calcitonin/chemistry
    • Humans
    • Molecular Dynamics Simulation
    • Peptides/chemistry
    • Protein Stability
    • Protein Structure, Quaternary
    • Protein Structure, Secondary


    Dive into the research topics of 'Nanostructure and stability of calcitonin amyloids'. Together they form a unique fingerprint.

    Cite this