Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor

Chris T. Middleton, Peter Marek, Ping Cao, Chi-cheng Chiu, Sadanand Singh, Ann Marie Woys, Juan J. De Pablo, Daniel P. Raleigh, Martin T. Zanni

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Amyloid formation has been implicated in the pathology of over 20 human diseases, but the rational design of amyloid inhibitors is hampered by a lack of structural information about amyloid-inhibitor complexes. We use isotope labelling and two-dimensional infrared spectroscopy to obtain a residue-specific structure for the complex of human amylin (the peptide responsible for islet amyloid formation in type 2 diabetes) with a known inhibitor (rat amylin). Based on its sequence, rat amylin should block formation of the C-terminal β-sheet, but at 8 h after mixing, rat amylin blocks the N-terminal β-sheet instead. At 24 h after mixing, rat amylin blocks neither β-sheet and forms its own β-sheet, most probably on the outside of the human fibrils. This is striking, because rat amylin is natively disordered and not previously known to form amyloid β-sheets. The results show that even seemingly intuitive inhibitors may function by unforeseen and complex structural processes.

Original languageEnglish
Pages (from-to)355-360
Number of pages6
JournalNature Chemistry
Volume4
Issue number5
DOIs
Publication statusPublished - 2012 May 1

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Islet Amyloid Polypeptide
Amyloid
Rats
Infrared spectroscopy
Pathology
Medical problems
Labeling
Peptides
Isotopes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Middleton, C. T., Marek, P., Cao, P., Chiu, C., Singh, S., Woys, A. M., ... Zanni, M. T. (2012). Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor. Nature Chemistry, 4(5), 355-360. https://doi.org/10.1038/nchem.1293
Middleton, Chris T. ; Marek, Peter ; Cao, Ping ; Chiu, Chi-cheng ; Singh, Sadanand ; Woys, Ann Marie ; De Pablo, Juan J. ; Raleigh, Daniel P. ; Zanni, Martin T. / Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor. In: Nature Chemistry. 2012 ; Vol. 4, No. 5. pp. 355-360.
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Middleton, CT, Marek, P, Cao, P, Chiu, C, Singh, S, Woys, AM, De Pablo, JJ, Raleigh, DP & Zanni, MT 2012, 'Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor', Nature Chemistry, vol. 4, no. 5, pp. 355-360. https://doi.org/10.1038/nchem.1293

Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor. / Middleton, Chris T.; Marek, Peter; Cao, Ping; Chiu, Chi-cheng; Singh, Sadanand; Woys, Ann Marie; De Pablo, Juan J.; Raleigh, Daniel P.; Zanni, Martin T.

In: Nature Chemistry, Vol. 4, No. 5, 01.05.2012, p. 355-360.

Research output: Contribution to journalArticle

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