Evidence for a partially structured state of the amylin monomer

Sara Vaiana, Robert B. Best, Wai Ming Yau, William A. Eaton, James Hofrichter

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Islet amyloid polypeptide (amylin) is the main component in amyloid deposits formed in type II diabetes. We used triplet quenching to probe the dynamics of contact formation between the N-terminal disulfide loop and a C-terminal tryptophan in monomeric amylins from human and rat. Quenching rates measured in the absence of denaturant are four times larger than those in 6 M guanidinium chloride, indicating a decrease in the average end-to-end distance (collapse) at low denaturant concentrations. We were surprised to find an even greater (sevenfold) increase in quenching rates on removal of denaturant for a hydrophilic control peptide containing the disulfide loop compared to the same peptide without the loop (twofold change). These results suggest that collapse is driven by backbone-backbone and backbone-side chain interactions involving the disulfide loop portion of the chain rather than by the formation of side-chain hydrophobic contacts. Molecular dynamics simulations of the control peptide show that the collapse results from hydrogen-bonding interactions between the central residues of the chain and the disulfide loop. The quenching experiments also indicate that the monomer of the human, amyloidogenic form of amylin is more compact than the rat form, which does not form amyloid. We discuss these newly observed differences between human and rat amylin in solution and their possible relation to aggregation and to the physiological function of amylin binding to the calcitonin receptor.

Original languageEnglish (US)
Pages (from-to)2948-2957
Number of pages10
JournalBiophysical Journal
Volume97
Issue number11
DOIs
StatePublished - Dec 2 2009

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Islet Amyloid Polypeptide
Disulfides
Peptides
Calcitonin Receptors
Guanidine
Amyloid Plaques
Molecular Dynamics Simulation
Hydrogen Bonding
Amyloid
Tryptophan
Type 2 Diabetes Mellitus

ASJC Scopus subject areas

  • Biophysics

Cite this

Vaiana, S., Best, R. B., Yau, W. M., Eaton, W. A., & Hofrichter, J. (2009). Evidence for a partially structured state of the amylin monomer. Biophysical Journal, 97(11), 2948-2957. https://doi.org/10.1016/j.bpj.2009.08.041

Evidence for a partially structured state of the amylin monomer. / Vaiana, Sara; Best, Robert B.; Yau, Wai Ming; Eaton, William A.; Hofrichter, James.

In: Biophysical Journal, Vol. 97, No. 11, 02.12.2009, p. 2948-2957.

Research output: Contribution to journalArticle

Vaiana, S, Best, RB, Yau, WM, Eaton, WA & Hofrichter, J 2009, 'Evidence for a partially structured state of the amylin monomer', Biophysical Journal, vol. 97, no. 11, pp. 2948-2957. https://doi.org/10.1016/j.bpj.2009.08.041
Vaiana, Sara ; Best, Robert B. ; Yau, Wai Ming ; Eaton, William A. ; Hofrichter, James. / Evidence for a partially structured state of the amylin monomer. In: Biophysical Journal. 2009 ; Vol. 97, No. 11. pp. 2948-2957.
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