Proislet Amyloid Polypeptide

Proislet Amyloid Polypeptide (proIAPP,Proamylin, Amyloid Polypeptide Precursor, Proislet Protein)

Proislet amyloid polypeptide (proIAPP) is the protein precursor for Islet amyloid polypeptide (IAPP, amylin) (Higham et al., 2001). ProIAPP is produced in the pancreatic beta cells (β-cells) as a 67 amino acid, 7404 Dalton pro-peptide and undergoes post-translational modifications to become the 37 amino acid IAPP hormone, also known as amylin. IAPP is cosecreted with insulin from the pancreatic β-cells in a ratio of approximately 100:1. Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

Structure and Synthesis


ProIAPP consists of 67 amino acids. The sequence (from N-terminus to C-terminus) is:

TPIESHQVEKRKCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTYGKRNAVEVLKREPLNYLPL (Higham et al., 2001).

Once produced by the β-cells, it undergoes proteolysis. 11 amino acids are removed from the N-terminus by the enzyme proprotein convertase 2 (PC2) while 16 are removed from the C-terminus of the proIAPP molecule by proprotein convertase 1/3 (PC1/3) (Sanke, Bell, Sample, Rubenstein, & Steiner, 1988). At the C-terminus Carboxypeptidase E then removes the terminal lysine and arginine residues (Marzban, Soukhatcheva, & Verchere, 2005). The terminal glycine amino acid that results from this cleavage allows the enzyme peptidylglycine alpha-amidating monooxygenase (PAM) to add an amine group. Finally, a disulfide bond is formed between cysteine residues numbers 2 and 7 (Roberts et al., 1989). After this the transformation from the precursor protein proIAPP to the biologically active IAPP is complete (IAPP sequence: KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY)(Higham et al., 2001).

Regulation
Insulin and IAPP are regulated by similar factors since they share a common regulatory promoter sequence (Höppener, Ahrén, & Cornelius, 2000). One of the defining features of Type 2 diabetes is insulin resistance. This is a condition wherein the body is unable to utilize insulin effectively, resulting in increased insulin production; since proinsulin and proIAPP are cosecreted, this results in an increase in the production of proIAPP as well.

Although little is known about IAPP regulation, its connection to insulin indicates that regulatory mechanism that affect insulin also affect IAPP. Thus blood glucose levels play an important role in regulation of proIAPP synthesis.

Role in Disease
ProIAPP has been linked to Type 2 diabetes and the loss of islet β-cells (Paulsson et al., 2005). Islet amyloid formation, initiated by the aggregation of proIAPP, may contribute to this progressive loss of islet β-cells. It is thought that proIAPP forms the first granules that allow for IAPP to aggregate and form amyloid which may lead to amyloid-induced apoptosis of β-cells.

IAPP is cosecreted with insulin. Insulin resistance in Type 2 diabetes produces a greater demand for insulin production which results in the secretion of proinsulin (Marzban, Rhodes, Haataja, Halban, & Verchere, 2006). ProIAPP is secreted simultaneously, however, the enzymes that convert these precursor molecules into insulin and IAPP, respectively, are not able to keep up with the high levels of secretion, ultimately leading to the accumulation of proIAPP.

In particular, the impaired processing of proIAPP that occurs at the N-terminal cleavage site is a key factor in the initiation of amyloid (Marzban et al., 2006). Post-translational modification of proIAPP occurs at both the carboxy terminus and the amino terminus, however, the processing of the amino terminus occurs later in the secretory pathway. This might be one reason why it is more susceptible to impaired processing under conditions where secretion is in high demand (Marzban et al., 2005). Thus, the conditions of Type 2 diabetes—high glucose concentrations and increased secretory demand for insulin and IAPP—could lead to the impaired N-terminal processing of proIAPP. The unprocessed proIAPP can then serve as the granule upon which IAPP can accumulate and form amyloid (Paulsson et al., 2006).

The amyloid formation might be a major mediator of apoptosis, or programmed cell death, in the islet β-cells (Paulsson et al., 2006). Initially, the proIAPP aggregates inside the cell. The proIAPP acts as a seed, collecting IAPP from neighboring cells and forming an intracellular amyloid. As the amyloid grows, it spreads outside of the cell. The extracellular amyloid begins to excrete IAPP to other cells, inducing similar amyloid formation in other β-cells. The overall effect is an apoptosis cascade initiated by the influx of ions into the β-cells.



In summary, impaired N-terminal processing of proIAPP is an important factor initiating amyloid formation and β-cell death. These amyloid deposits are pathological characteristics of the pancreas in Type 2 diabetes. However, it is still unclear as to whether amyloid formation is involved in or merely a consequence of type 2 diabetes (Marzban et al., 2006). Nevertheless it is clear that amyloid formation reduces working β-cells in patients with Type 2 diabetes. This suggests that repairing proIAPP processing may help to prevent β-cell death, thereby offering hope as a potential therapeutic approach for Type 2 diabetes.