Nanostructure and stability of calcitonin amyloids

Federica Rigoldi, Pierangelo Metrangolo, Alberto Redaelli, Alfonso Gautieri

Research output: Contribution to journalArticleScientificpeer-review

4 Citations (Scopus)

Abstract

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 ß-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp15 to Phe19 of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel ß-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 a-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 Asp15 and Phe19 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 ß-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 ß-sheet packing.
Original languageEnglish
Pages (from-to)7348-7357
Number of pages10
JournalJournal of Biological Chemistry
Volume292
Issue number18
DOIs
Publication statusPublished - 2017
MoE publication typeA1 Journal article-refereed

Fingerprint

Nanostructures
Calcitonin
Amyloid
Peptides
Conformations
Molecular Dynamics Simulation
Molecular dynamics
Stabilization
Thyroid Hormones
Nuclear magnetic resonance
Amino Acids
Molecules
Computer simulation

Cite this

Rigoldi, F., Metrangolo, P., Redaelli, A., & Gautieri, A. (2017). Nanostructure and stability of calcitonin amyloids. Journal of Biological Chemistry, 292(18), 7348-7357. https://doi.org/10.1074/jbc.M116.770271
Rigoldi, Federica ; Metrangolo, Pierangelo ; Redaelli, Alberto ; Gautieri, Alfonso. / Nanostructure and stability of calcitonin amyloids. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 18. pp. 7348-7357.
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abstract = "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 {\ss}-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp15 to Phe19 of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel {\ss}-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 a-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 Asp15 and Phe19 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 {\ss}-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 {\ss}-sheet packing.",
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Rigoldi, F, Metrangolo, P, Redaelli, A & Gautieri, A 2017, 'Nanostructure and stability of calcitonin amyloids', Journal of Biological Chemistry, vol. 292, no. 18, pp. 7348-7357. https://doi.org/10.1074/jbc.M116.770271

Nanostructure and stability of calcitonin amyloids. / Rigoldi, Federica; Metrangolo, Pierangelo; Redaelli, Alberto; Gautieri, Alfonso.

In: Journal of Biological Chemistry, Vol. 292, No. 18, 2017, p. 7348-7357.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Nanostructure and stability of calcitonin amyloids

AU - Rigoldi, Federica

AU - Metrangolo, Pierangelo

AU - Redaelli, Alberto

AU - Gautieri, Alfonso

PY - 2017

Y1 - 2017

N2 - 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 ß-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp15 to Phe19 of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel ß-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 a-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 Asp15 and Phe19 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 ß-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 ß-sheet packing.

AB - 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 ß-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp15 to Phe19 of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel ß-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 a-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 Asp15 and Phe19 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 ß-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 ß-sheet packing.

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DO - 10.1074/jbc.M116.770271

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EP - 7357

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

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