Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology

Abstract

Amyloid formation in the pancreas by islet amyloid polypeptide (IAPP) leads to β-cell death and dysfunction, contributing to islet transplant failure and to type-2 diabetes. IAPP is stored in the β-cell insulin secretory granules and cosecreted with insulin in response to β-cell secretagogues. IAPP is believed to play a role in the control of food intake, in controlling gastric emptying and in glucose homeostasis. The polypeptide is natively unfolded in its monomeric state, but is one of the most amyloidogenic sequences known. The mechanisms of IAPP amyloid formation in vivo and in vitro are not understood; the mechanisms of IAPP induced cell death are unclear; and the nature of the toxic species is not completely defined. Recent work is shedding light on these important issues.

Figure 1

Post translational modification of human PreProIAPP to form the mature IAPP sequence: (a) The primary sequence of the 89-residue human PreProIAPP. The 22 residue signaling sequence is shown in black, the N-terminal and C-terminal proIAPP flanking regions are shown in blue, and the mature IAPP sequence is shown in red. (b) The primary sequence of the 67-residue human proIAPP. Before secretion, proIAPP is cleaved by the prohormone convertases PC2 and PC(1/3) at two dibasic sites, indicated by arrows. Further processing by the CPE/PAM complex results in an amidated Tyr at the C-terminus of mature IAPP. (c) The mature 37-residue human IAPP. The biologically active peptide has an intramolecular disulfide bridge between Cys-2 and Cys-7 and an amidated C-terminus. Positively charged residues are underlined in the ProIAPP and mature IAPP sequences.

Figure 2

Primary sequences of IAPP from different species: residues that differ from the human sequence are underlined and highlighted in red. Only partial sequences are available for rabbit and hare. The biologically active mature sequence has a disulfide bridge between Cys-2 and Cys-7 and an amidated C-terminus. Primates and cats have been reported to form islet amyloid while dogs, rodents and cows do not. Porcine and ferret IAPP are significantly less amyloidogenic than human IAPP. The degue forms islet amyloid, but the deposits are derived from aggregation of insulin, not IAPP.

Figure 3

The structure of human IAPP: (a) The primary sequence of human IAPP. Residues 8–17 form intermolecular β-sheets in models of the IAPP amyloid fiber and are color coded in red. Residues 18–22, colored in green, form a bend in the UCLA model while residues 23–37, colored in blue, take part in an intermolecular β-sheet. The color coding corresponds to the IAPP amyloid structural model developed by the UCLA group [23]. The first 7 residues do not take part in β-sheet structure in existing models of IAPP amyloid. (b) A structural model of the IAPP fiber developed by the UCLA group [23]. Two views are shown: a top down view and an image rotated by 90 degrees. The color coding corresponds to that used in panel A. (c) A view of one layer of the stacked structure shown in panel (b). His-18, Ser-20, Ser-28, Ser-29, Thr-30 are shown in space-filling representation. The protonation state of His-18 affects the rate of amyloid formation [77]. A Ser-20 to Gly mutant is the only reported mutation in mature IAPP found in humans and has been shown to accelerate amyloid formation [4,11]. Ser-28, Ser-29 and Thr-30 form key inter-peptide contacts in the UCLA model. IAPP contains three aromatic residues (Phe-15, Phe-23, and Tyr-37) which are also highlighted.