Mutational analysis of preamyloid intermediates: The role of His-Tyr interactions in islet amyloid formation

Ling Hsien Tu, Arnaldo L. Serrano, Martin T. Zanni, Daniel P. Raleigh

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Islet amyloid polypeptide (IAPP or Amylin) is a 37-residue, C-terminally amidated pancreatic hormone, cosecreted with insulin that forms islet amyloid in type 2 diabetes. Islet amyloid formation is complex and characterizing preamyloid oligomers is an important topic because oligomeric intermediates are postulated to be the most toxic species produced during fibril formation. A range of competing models for early oligomers have been proposed. The role of the amidated C-terminus in amyloid formation by IAPP and in stabilizing oligomers is not known. Studies with unamidated IAPP have provided evidence for formation of an antiparallel dimer at pH 5.5, stabilized by stacking of His-18 and Tyr-37, but it is not known if this interaction is formed in the physiological form of the peptide. Analysis of a set of variants with a free and with an amidated C-terminus shows that disrupting the putative His-Tyr interaction accelerates amyloid formation, indicating that it is not essential. Amidation to generate the physiologically relevant form of IAPP accelerates amyloid formation, demonstrating that the advantages conferred by C-terminal amidation outweigh increased amyloidogenicity. The analysis of this variant argues that IAPP is not under strong evolutionary pressure to reduce amyloidogenicity. Analysis of an H18Q mutant of IAPP shows that the charge state of the N-terminus is an important factor controlling the rate of amyloid formation, even though the N-terminal region of IAPP is believed to be flexible in the amyloid fibers.

Original languageEnglish
Pages (from-to)1520-1527
Number of pages8
JournalBiophysical Journal
Volume106
Issue number7
DOIs
Publication statusPublished - 2014 Apr 1

ASJC Scopus subject areas

  • Biophysics

Fingerprint Dive into the research topics of 'Mutational analysis of preamyloid intermediates: The role of His-Tyr interactions in islet amyloid formation'. Together they form a unique fingerprint.

Cite this