Residual Structure in Islet Amyloid Polypeptide Mediates Its Interactions with Soluble Insulin†
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- 作者：Lei Wei ; Ping Jiang ; Yin Hoe Yau ; Heike Summer ; Susana Geifman Shochat ; Yuguang Mu* ; Konstantin Pervushin*
- 刊名：Biochemistry
- 出版年：2009
- 出版时间：March 24, 2009
- 年：2009
- 卷：48
- 期：11
- 页码：2368-2376
- 全文大小：276K
- 年卷期：v.48,no.11(March 24, 2009)
- ISSN：1520-4995
文摘
Islet amyloid polypeptide (IAPP), a 37-amino acid polypeptide hormone of the calcitonin family, is colocalized and cosecreted with insulin in secretory granules of pancreatic islet β cells. IAPP can assemble into toxic oligomers and amyloid fibrils, a hallmark of type 2 diabetes. Its interactions with insulin in the secretory granules might influence the formation of cytotoxic oligomers and amyloid fibrils. Presented NMR analysis shows that IAPP, free in solution and in complex with insulin, retains elements of residual secondary structure. NMR chemical shifts and 15N relaxation data as well as 49 ns replica exchange molecular dynamic simulations indicate that the transiently populated helical structure in residues 11−18 is essential for interactions with insulin. These interactions are mediated by salt bridges between positively charged residues Arg11 or Arg18 of rat IAPP and Glu13 of insulin B chain as well as by hydrophobic interactions flanking the salt bridges. The insulin binding region is composed of the same amino acids in amyloidogenic human IAPP and soluble rat IAPP (with the sole exception of His/Arg-18), implying the same binding mode for both hormones. This His/Arg-18 mutation results in reduced affinity binding of human IAPP to insulin in comparison to rat IAPP as it is detected by surface plasmon resonance biosensor analysis. Implications of the described interactions between soluble forms of IAPP and insulin in preventing oligomerization of human IAPP are discussed.