Amyloidogenicity of recombinant human pro-islet amyloid polypeptide (ProIAPP)

Krampert, Monika; Bernhagen, Jürgen; Schmucker, Jürgen; Horn, Anita; Schmauder, Anke; Brunner, Herwig; Voelter, Wolfgang; Kapurniotu, Aphrodite

doi:10.1016/s1074-5521(00)00034-x

Cited by 40 publications

(50 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An increase in production of proIAPP-like molecules could affect IAPP aggregation by several mechanisms. Firstly, proIAPP has been shown to form amyloid-like fibrils in vitro although with less avidity than IAPP [77]. Secondly, it has been shown that a synthetic construct of proIAPP with the N-terminal cleavage fragment intact, readily binds to heparan sulphate but IAPP does not [78].…”

Section: Aberrant Prohormone Processingmentioning

confidence: 99%

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

2004

View full text Add to dashboard Cite

The role of islet amyloidosis in the onset and progression of Type 2 diabetes remains obscure. Islet amyloid polypeptide is a 37 amino-acid, beta-cell peptide which is co-stored and co-released with insulin. Human islet amyloid polypeptide refolds to a β-conformation and oligomerises to form insoluble fibrils; proline substitutions in rodent islet amyloid polypeptide prevent this molecular transition. Pro-islet amyloid polypeptide (67 amino acids in man) is processed in secretory granules. Refolding of islet amyloid polypeptide may be prevented by intragranular heterodimer formation with insulin (but not proinsulin). Diabetes-associated abnormal proinsulin processing could contribute to de-stabilisation of granular islet amyloid polypeptide. Increased pro-islet amyloid polypeptide secretion as a consequence of islet dysfunction could promote fibrillogenesis; the propeptide forms fibrils and binds to basement membrane glycosamino-glycans. Islet amyloid polypeptide gene polymorphisms are not universally associated with Type 2 diabetes. Transgenic mice expressing human islet amyloid polypeptide gene have increased islet amyloid polypeptide concentrations but develop islet amyloid only against a background of obesity and/or high fat diet. In transgenic mice, obese monkeys and cats, initially small perivascular deposits progressively increase to occupy 80% islet mass; the severity of amyloidosis in animal models is related to the onset of hyperglycaemia, suggesting that islet amyloid and the associated destruction of islet cells cause diabetes. In human diabetes, islet amyloid can affect less than 1% or up to 80% of islets indicating that islet amyloidosis largely results from diabetes-related pathologies and is not an aetiological factor for hyperglycaemia. However, the associated progressive betacell destruction leads to severe islet dysfunction and insulin requirement. [Diabetologia (2004) 47:157-169]

show abstract

Section: Aberrant Prohormone Processingmentioning

confidence: 99%

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

2004

View full text Add to dashboard Cite

show abstract

“…Although not understood on a mechanistic level, impairment of prohormone processing has been thought to play a role in initiation and progression of T2D (22,23). Insulin and pro-IAPP (22,(24)(25)(26), but not proinsulin, can inhibit IAPP amyloid formation in vitro and in mice, suggesting that accumulation of unprocessed proinsulin may promote IAPP amyloid formation (22,24). Insulin-degrading enzyme (IDE) is a conserved metallopeptidase that can degrade insulin and a variety of other small peptides including IAPP in the pancreas (27,28).…”

mentioning

confidence: 99%

Cross-talk between amyloidogenic proteins in type-2 diabetes and Parkinson’s disease

Horváth

Wittung-Stafshede

2016

Proc. Natl. Acad. Sci. U.S.A.

132

125

View full text Add to dashboard Cite

In type-2 diabetes (T2D) and Parkinson's disease (PD), polypeptide assembly into amyloid fibers plays central roles: in PD, α-synuclein (aS) forms amyloids and in T2D, amylin [islet amyloid polypeptide (IAPP)] forms amyloids. Using a combination of biophysical methods in vitro we have investigated whether aS, IAPP, and unprocessed IAPP, pro-IAPP, polypeptides can cross-react. Whereas IAPP forms amyloids within minutes, aS takes many hours to assemble into amyloids and pro-IAPP aggregates even slower under the same conditions. We discovered that preformed amyloids of pro-IAPP inhibit, whereas IAPP amyloids promote, aS amyloid formation. Amyloids of aS promote pro-IAPP amyloid formation, whereas they inhibit IAPP amyloid formation. In contrast, mixing of IAPP and aS monomers results in coaggregation that is faster than either protein alone; moreover, pro-IAPP can incorporate aS monomers into its amyloid fibers. From this intricate network of cross-reactivity, it is clear that the presence of IAPP can accelerate aS amyloid formation. This observation may explain why T2D patients are susceptible to developing PD.α-synuclein | fluorescence | amyloid | atomic force microscopy | amylin

show abstract

“…It is known that synthetic proIAPP can aggregate and form amyloid-like fibrils (30). Therefore, increased concentrations of proIAPP or IAPP intermediates could theoretically predispose to intracellular amyloid formation and thus represent the initial site for amyloid deposition.…”

mentioning

confidence: 99%

Aberrant Processing of Human Proislet Amyloid Polypeptide Results in Increased Amyloid Formation

2005

View full text Add to dashboard Cite

The amyloid present in the islets of Langerhans in type 2 diabetes is polymerized islet amyloid polypeptide (IAPP). The precursor protein proIAPP is posttranslationally modified, a process involving the removal of NH 2 -and COOH-terminal flanking peptides. This step is performed by the prohormone convertases PC2 and PC1/3. PC2 processes proIAPP preferably at the NH 2 -terminal processing site, and PC1/3 processes proIAPP exclusively at the COOH-terminal site. Little is known regarding the exact circumstances leading to islet amyloid formation. In this study, we have examined the possible significance of aberrant processing of proIAPP on amyloid formation in several in vitro cellular systems. In our studies, human (h)-proIAPP was transfected into ␤-TC-6 cells expressing both prohormone convertases and in which proIAPP is processed into IAPP. Additionally P ancreatic islet amyloid is a frequent and characteristic pathological feature of type 2 diabetes. The amount of amyloid deposited varies, but it is present to some degree in 40 -95% of the patients (1-3), and a decrease in the number of ␤-cells follows the accumulation of islet amyloid (4 -6). The main amyloid constituent is the 37-amino acid polypeptide hormone islet amyloid polypeptide (IAPP) (7) or amylin (8). This ␤-cell product is stored (9) and released together with insulin upon stimulation (10,11). In humans, IAPP is synthesized as a 67-amino acid proIAPP molecule from which NH 2 -terminal and COOH-terminal flanking peptides are subsequently removed proteolytically (12). This posttranslational processing within the secretory granules occurs at di-basic amino acids and is performed by the prohormone convertases 2 and 1/3 (PC2 and PC1/3). These are the same enzymes that process proinsulin to insulin at the same cellular location (13). In in vitro studies on the processing of human proIAPP (h-proIAPP) by recombinant converting enzymes, PC2 favored processing at the NH 2 -terminal flanking region and PC1/3 had its initial activity at the COOH-terminal region. However, during extended incubation time, both PC2 and PC1/3 could, to some degree, process proIAPP at both cleavage sites (14). In contrast, the in vivo results from studies on the processing of proIAPP performed in PC2 (15) and PC1/3 (16) null mice showed that PC2 is required for cleavage at the NH 2 -terminal region and that PC1/3 processes the COOHterminal flanking region. However, in the absence of PC1/3, this cleavage site can be processed by PC2.Little is known about the mechanisms that precede the deposition of islet amyloid. The use of human IAPP (h-IAPP)-expressing transgenic animals has demonstrated that increased expression of IAPP by itself is not sufficient for amyloid to develop (17-19). However, introduction of the h-IAPP gene into mouse strains with diabetic traits resulted in the formation of islet amyloid (20,21). Amyloid was also detected in transgenic animals fed a high-fat diet (22). In mouse IAPP (mIAPP)-null mice expressing the gene for h-IAPP, amyloid developed within 9 months ...

show abstract

Amyloidogenicity of recombinant human pro-islet amyloid polypeptide (ProIAPP)

Abstract: Our studies suggest that ProIAPP has typical properties of an amyloidogenic polypeptide but also indicate that the pro-region suppresses the amyloidogenic and cytotoxic potentials of IAPP.

Cited by 40 publications

References 74 publications

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

Cross-talk between amyloidogenic proteins in type-2 diabetes and Parkinson’s disease

Aberrant Processing of Human Proislet Amyloid Polypeptide Results in Increased Amyloid Formation

Contact Info

Product

Resources

About