Abstract
IAPP, a 37 amino-acid peptide hormone belonging to the calcitonin family, is an intrinsically disordered protein that is coexpressed and cosecreted along with insulin by pancreatic islet β-cells in response to meals. IAPP plays a physiological role in glucose regulation; however, in certain species, IAPP can aggregate and this process is linked to β-cell death and Type II Diabetes. Using replica exchange molecular dynamics with extensive sampling (16 replicas per sequence and 600 ns per replica), we investigate the structure of the monomeric state of two species of aggregating peptides (human and cat IAPP) and two species of non-aggregating peptides (pig and rat IAPP). Our simulations reveal that the pig and rat conformations are very similar, and consist of helix-coil and helix-hairpin conformations. The aggregating sequences, on the other hand, populate the same helix-coil and helix-hairpin conformations as the non-aggregating sequence, but, in addition, populate a hairpin structure. Our exhaustive simulations, coupled with available peptide-activity data, leads us to a structure-activity relationship (SAR) in which we propose that the functional role of IAPP is carried out by the helix-coil conformation, a structure common to both aggregating and non-aggregating species. The pathological role of this peptide may have multiple origins, including the interaction of the helical elements with membranes. Nonetheless, our simulations suggest that the hairpin structure, only observed in the aggregating species, might be linked to the pathological role of this peptide, either as a direct precursor to amyloid fibrils, or as part of a cylindrin type of toxic oligomer. We further propose that the helix-hairpin fold is also a possible aggregation prone conformation that would lead normally non-aggregating variants of IAPP to form fibrils under conditions where an external perturbation is applied. The SAR relationship is used to suggest the rational design of therapeutics for treating diabetes.
Highlights
The Islet Amyloid Polypeptide/IAPP is coexpressed and cosecreted with insulin by pancreatic islet b-cells [1,2,3] and acts as a synergistic partner of insulin to limit after-meal glucose excursions [4]
IAPP, a 37 amino-acid peptide hormone belonging to the calcitonin family, is an intrinsically disordered peptide produced along with insulin by pancreatic islet b-cells in response to meals
In its functional form, IAPP acts as a synergic partner of insulin to reduce blood glucose
Summary
The Islet Amyloid Polypeptide/IAPP ( known as amylin) is coexpressed and cosecreted with insulin by pancreatic islet b-cells [1,2,3] and acts as a synergistic partner of insulin to limit after-meal glucose excursions [4]. The CT peptides function as hormones and are distributed in various peripheral tissues (the endocrine pancreas in the case of IAPP), and play important biological roles including reducing nutrient intake (IAPP), decreasing bond resorption (Calcitonin) and vasodilatation (CGRP/calcitonin gene-related peptide). These functions are fulfilled through hormone-receptor agonism in which the CT peptide binds to a signal transduction membrane protein complex and thereby induces cell response in peripheral tissues. In the particular case of IAPP, this peptide binds to multiple amylinspecific (AMY) receptor complexes [1,7,8,9,10]. CT peptides show strong sequence homology in their two terminal regions (residues 1–19 and 30–37), and shares three features: [7] an N-terminal disulfide bond, an N-terminal amphipathic region, and C-terminal amidation
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