Residual structure in islet amyloid polypeptide mediates its interactions with soluble insulin.
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 beta 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 (15)N 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.
Wei
Lei
L
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Jiang
Ping
P
Yau
Yin Hoe
YH
Summer
Heike
H
Shochat
Susana Geifman
SG
Mu
Yuguang
Y
Pervushin
Konstantin
K
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006801:Humans; D007328:Insulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D058228:Islet Amyloid Polypeptide; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011485:Protein Binding; D051381:Rats; D012995:Solubility
D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide