Abstract
Aim: To identify naturally occurring variants of IAPP capable of inhibiting the aggregation of human IAPP and protecting living cells from the toxic effects of human IAPP.
Background: The loss of insulin-producing β-cells and the overall progression of type 2 diabetes appears to be linked to the formation of toxic human IAPP (hIAPP, Islet Amyloid Polypeptide, amylin) amyloid in the pancreas. Inhibiting the initial aggregation of hIAPP has the potential to slow, if not stop entirely, the loss of β-cells and halt the progression of the disease.
Objective: To identify and characterize naturally occurring variants of IAPP capable of inhibiting human IAPP aggregation.
Methods: Synthetic human IAPP was incubated with synthetic IAPP variants identified from natural sources under conditions known to promote amyloid-based aggregation. To identify IAPP variants capable of inhibiting human IAPP aggregation, Thioflavin T-binding fluorescence, atomic force microscopy, and cell-rescue assays were performed.
Results: While most IAPP variants showed little to no ability to inhibit human IAPP aggregation, several variants showed some ability to inhibit aggregation, with two variants showing substantial inhibitory potential.
Conclusion: Several naturally occurring IAPP variants capable of inhibiting human IAPP aggregation were identified and characterized.
Keywords: Islet amyloid polypeptide, protein aggregation, amyloid, type 2 diabetes, amylin, pancreas.
Graphical Abstract
[1]
Montane, J.; Klimek-Abercrombie, A.; Potter, K.J.; Westwell-Roper, C.; Bruce Verchere, C. Metabolic stress, IAPP and islet amyloid. Diabetes Obes. Metab., 2012, 14(Suppl. 3), 68-77.[http://dx.doi.org/10.1111/j.1463-1326.2012.01657.x] [PMID: 22928566]
[2]
Asthana, S.; Mallick, B.; Alexandrescu, A.T.; Jha, S. IAPP in type II diabetes: Basic research on structure, molecular interactions, and disease mechanisms suggests potential intervention strategies. Biochim. Biophys. Acta, 2018, 1860(9), 1765-1782.[http://dx.doi.org/10.1016/j.bbamem.2018.02.020] [PMID: 29518374]
[3]
Paulsson, J.F.; Ludvigsson, J.; Carlsson, A. High plasma levels of islet amyloid polypeptide in young with new-onset of type 1 diabetes mellitus. PLoS One, 2014, 9(3), e93053.[http://dx.doi.org/10.1371/journal.pone.0093053]
[4]
Ling, W.; Huang, Y.M.; Qiao, Y.C.; Zhang, X.X.; Zhao, H.L. Human amylin: From pathology to physiology and pharmacology. Curr. Protein Pept. Sci., 2019, 20(9), 944-957.[http://dx.doi.org/10.2174/1389203720666190328111833] [PMID: 30919775]
[5]
Cao, P.; Abedini, A.; Raleigh, D.P. Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology. Curr. Opin. Struct. Biol., 2013, 23(1), 82-9.[http://dx.doi.org/10.1016/j.sbi.2012.11.003]
[6]
Bucciantini, M.; Giannoni, E.; Chiti, F. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature, 2002, 416(6880), 507-511.[http://dx.doi.org/10.1038/416507a]
[7]
Chiti, F.; Dobson, C.M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem., 2006, 75, 333-366.[http://dx.doi.org/10.1146/annurev.biochem.75.101304.123901]
[8]
Murphy, R.M.; Kendrick, B.S. Protein misfolding and aggregation. Biotechnol. Prog., 2007, 23(3), 548-552.[http://dx.doi.org/10.1021/bp060374h]
[9]
Abedini, A.; Schmidt, A.M. Mechanisms of islet amyloidosis toxicity in type 2 diabetes. FEBS Lett., 2013, 587(8), 1119-1127.[http://dx.doi.org/10.1016/j.febslet.2013.01.017]
[10]
Apostolidou, M.; Jayasinghe, S.A.; Langen, R. Structure of alpha-helical membrane-bound human islet amyloid polypeptide and its implications for membrane-mediated misfolding. J. Biol. Chem., 2008, 283(25), 17205-17210.[http://dx.doi.org/10.1074/jbc.M801383200] [PMID: 18442979]
[11]
Hull, R.L.; Westermark, G.T.; Westermark, P.; Kahn, S.E. Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J. Clin. Endocrinol. Metab., 2004, 89(8), 3629-3643.[http://dx.doi.org/10.1210/jc.2004-0405] [PMID: 15292279]
[12]
Kahn, S.E.; Andrikopoulos, S.; Verchere, C.B. Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes, 1999, 48(2), 241-253.[http://dx.doi.org/10.2337/diabetes.48.2.241]
[13]
Patel, H.R.; Pithadia, A.S.; Brender, J.R.; Fierk, C.A.; Ramamoorthy, A. In search of aggregation pathways of IAPP and other amyloidogenic proteins: finding answers through NMR spectroscopy. J. Phys. Chem. Lett., 2014, 5(11), 1864-1870.[http://dx.doi.org/10.1021/jz5001775] [PMID: 26273866]
[14]
Moore, S.J.; Sonar, K.; Bharadwaj, P. Characterisation of the structure and oligomerisation of islet amyloid polypeptides (IAPP): a review of molecular dynamics simulation studies. Molecules, 2018, 23(9), 2142.[http://dx.doi.org/10.3390/molecules23092142] [PMID: 30149632]
[15]
Westermark, P.; Engstrom, U.; Johnson, K.H. Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc. Natl. Acad. Sci. USA, 1990, 87(13), 5036-5040.[http://dx.doi.org/10.1073/pnas.87.13.5036]
[16]
Fortin, J.S.; Benoit-Biancamano, M.O. Wildlife sequences of islet amyloid polypeptide (IAPP) identify critical species variants for fibrillization. Amyloid, 2015, 22(3), 194-202.[http://dx.doi.org/10.3109/13506129.2015.1070824] [PMID: 26300107]
[17]
Betsholtz, C.; Christmanson, L.; Engstrom, U.; Rorsman, F.; Jordan, K.; O'Brien, T.D.; Murtaugh, M.; Johnson, K.H.; Westermark, P. Structure of cat islet amyloid polypeptide and identification of amino-acid-residues of potential significance for islet amyloid formation. Diabetes, 1990, 39(1), 118-122.[http://dx.doi.org/10.2337/diacare.39.1.118] [PMID: 2210054]
[18]
Palato, L.M.; Pilcher, S; Oakes, A; Lamba, A.; Torres, J.; Ledesma Monjaraz, L.I.; Munoz, C.; Njoo, E.; Rinauro, D.J.; Menefee, K.A.; Tun, A.; Jauregui, B.L.; Shapiro, S.; Nossiff, O.H.; Olivares, E.; Chang, K.; Nguyen, V.; Nogaj, L.A.; Moffet, D.A. Amyloidogenicity of naturally occurring full-length animal IAPP variants. J. Pept. Sci., 2019, 25(8), e3199.[http://dx.doi.org/10.1002/psc.3199] [PMID: 31231935]
[19]
Denroche, H.C.; Verchere, C.B. IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants. J. Mol. Endocrinol., 2018, 60(2), R57-R75.[http://dx.doi.org/10.1530/JME-17-0138] [PMID: 29378867]
[20]
Suzuki, S.; Murakami, M.; Abe, S.; Satoh, Y.; Shintani, S.; Ishizuka, J.; Suzuki, K.; Thompson, J.C.; Toyota, T. The effects of amylin on insulin secretion from Rin m5F cells and glycogen synthesis and lipogenesis in rat primary cultured hepatocytes. Diabetes Res. Clin. Pract., 1992, 15(1), 77-84.[http://dx.doi.org/10.1016/0168-8227(92)90071-X] [PMID: 1311671]
[21]
Higham, C.E.; Jaikaran, E.T.; Fraser, P.E.; Gross, M.; Clark, A. Preparation of synthetic human islet amyloid polypeptide (IAPP) in a stable conformation to enable study of conversion to amyloid-like fibrils. FEBS Lett., 2000, 470(1), 55-60.[http://dx.doi.org/10.1016/S0014-5793(00)01287-4] [PMID: 10722845]
[22]
Wong, A.G.; Wu, C.; Hannaberry, E. Analysis of the amyloidogenic potential of pufferfish (Takifugu rubripes) islet amyloid polypeptide highlights the limitations of thioflavin-t assays and the difficulties in defining amyloidogenicity. Biochemistry, 2016, 55(3), 510-518.[http://dx.doi.org/10.1021/acs.biochem.5b01107] [PMID: 26694855]
[23]
Kayed, R.; Bernhagen, J.; Greenfield, N.; Sweimeh, K.; Brunner, H.; Voelter, W.; Kapurniotu, A. Conformational transitions of islet amyloid polypeptide (IAPP) in amyloid formation in vitro. J. Mol. Biol., 1999, 287(4), 781-796.[http://dx.doi.org/10.1006/jmbi.1999.2646] [PMID: 10191146]
[24]
Watanabe-Nakayama, T.; Sahoo, B.R.; Ramamoorthy, A. High-speed atomic force microscopy reveals the structural dynamics of the amyloid-beta and amylin aggregation pathways. Int. J. Mol. Sci., 2020, 21(12), 4287.
[25]
Berhanu, W.M.; Hansmann, U.H. Inter-species cross-seeding: stability and assembly of rat-human amylin aggregates. PLoS One, 2014, 9(5), e97051.
[26]
Middleton, C.T.; Marek, P.; Cao, P. Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor. Nat. Chem., 2012, 5(4), 355-360.[http://dx.doi.org/10.1038/nchem.1293]
[27]
Zhang, M.; Hu, R.; Liang, G.; Chang, Y.; Sun, Y.; Peng, Z.; Zheng, J. Structural and energetic insight into the cross-seeding amyloid assemblies of human IAPP and rat IAPP. J. Phys. Chem. B, 2014, 118(25), 7026-7036.[http://dx.doi.org/10.1021/jp5022246] [PMID: 24892388]
[28]
Liang, G.; Zhao, J.; Yu, X.; Zheng, J. Comparative molecular dynamics study of human islet amyloid polypeptide (IAPP) and rat IAPP oligomers. Biochemistry, 2013, 52(6), 1089-1100.[http://dx.doi.org/10.1021/bi301525e] [PMID: 23331123]
[29]
Mazzaglia, A.; Micali, N.; Scolaro, L.M.; Attanasio, F.; Magrí, A.; Pappalardo, G.; Villari, V. Aggregation properties of the peptide fragments derived from the 17-29 region of the human and rat IAPP: a comparative study with two PEG-conjugated variants of the human sequence. J. Phys. Chem. B, 2010, 114(2), 705-713.[http://dx.doi.org/10.1021/jp908436s] [PMID: 20039665]
[30]
Fox, A.; Snollaerts, T.; Casanova, C.E. Selection for nonamyloidogenic mutants of islet amyloid polypeptide (IAPP) identifies an extended region for amyloidogenicity. Biochemistry, 2010, 49(36), 7783-7789.
[31]
Gazit, E. Mechanisms of amyloid fibril self-assembly and inhibition. FEBS J., 2005, 272(23), 5971-5978.[http://dx.doi.org/10.1111/j.1742-4658.2005.05022.x]
[32]
Nanga, R.P.; Brender, J.R.; Xu, J.; Veglia, G.; Ramamoorthy, A. Structures of rat and human islet amyloid polypeptide IAPP(1-19) in micelles by NMR spectroscopy. Biochemistry, 2008, 47(48), 12689-12697.[http://dx.doi.org/10.1021/bi8014357] [PMID: 18989932]
[33]
Abedini, A.; Raleigh, D.P. Destabilization of human IAPP amyloid fibrils by proline mutations outside of the putative amyloidogenic domain: is there a critical amyloidogenic domain in human IAPP? J Mol Biol., 2006, 355(2), 274-281.
[34]
Marek, P.; Abedini, A.; Song, B.B. Aromatic interactions are not required for amyloid fibril formation by islet amyloid polypeptide but do influence the rate of fibril formation and fibril morphology. Biochemistry, 2007, 4611, 3255-3261.[http://dx.doi.org/10.1021/bi0621967]
[35]
Abedini, A.; Meng, F.L.; Raleigh, D.P. A single-point mutation converts the highly amyloidogenic human islet amyloid polypeptide into a potent fibrillization inhibitor. J. Am. Chem. Soc., 2007, 129(37), 11300.[http://dx.doi.org/10.1021/ja072157y]
[36]
Abedini, A.; Raleigh, D.P. The role of His-18 in amyloid formation by human islet amyloid polypeptide. Biochemistry, 2005, 44(49), 16284-16291.[http://dx.doi.org/10.1021/bi051432v]
[37]
Koo, B.W.; Hebda, J.A.; Miranker, A.D. Amide inequivalence in the fibrillar assembly of islet amyloid polypeptide. Protein Eng. Des. Sel., 2008, 21(3), 147-154.[http://dx.doi.org/10.1093/protein/gzm076]
[38]
Scrocchi, L.A.; Chen, Y.; Waschuk, S. Design of peptide-based inhibitors of human islet amyloid polypeptide fibrillogenesis. J. Mol. Biol., 2002, 318(3), 697-706.[http://dx.doi.org/10.1016/S0022-2836(02)00164-X]
[39]
Tracz, S.M.; Abedini, A.; Driscoll, M.; Raleigh, D.P. Role of aromatic interactions in amyloid formation by peptides derived from human Amylin. Biochemistry, 2004, 43(50), 15901-15908.[http://dx.doi.org/10.1021/bi048812l] [PMID: 15595845]
[40]
Park, J.Y.; Lansbury, P.T. Jr. Beta-synuclein inhibits formation of alpha-synuclein protofibrils: A possible therapeutic strategy against Parkinson’s disease. Biochemistry, 2003, 42(13), 3696-3700.[http://dx.doi.org/10.1021/bi020604a] [PMID: 12667059]
[41]
Kessler, J.C.; Rochet, J.C.; Lansbury, P.T., Jr The N-terminal repeat domain of alpha-synuclein inhibits beta-sheet and amyloid fibril formation. Biochemistry, 2003, 42(3), 672-678.[http://dx.doi.org/10.1021/bi020429y] [PMID: 12534279]
[42]
Rochet, J.C.; Conway, K.A.; Lansbury, P.T., Jr Inhibition of fibrillization and accumulation of prefibrillar oligomers in mixtures of human and mouse alpha-synuclein. Biochemistry, 2000, 39(35), 10619-10626.[http://dx.doi.org/10.1021/bi001315u] [PMID: 10978144]
[43]
Uversky, V.N.; Li, J.; Souillac, P.; Millett, I.S.; Doniach, S.; Jakes, R.; Goedert, M.; Fink, A.L. Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins. J. Biol. Chem., 2002, 277(14), 11970-11978.[http://dx.doi.org/10.1074/jbc.M109541200] [PMID: 11812782]
[44]
Kanatsuka, A.; Kou, S.; Makino, H. IAPP/amylin and beta-cell failure: implication of the risk factors of type 2 diabetes. Diabetol Int., 2018, 9(3), 143-157.[http://dx.doi.org/10.1007/s13340-018-0347-1]
[45]
Kim, J.; Park, K.; Kim, M.J. An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer. Nat Commun., 2021, 12(1), 183.[http://dx.doi.org/10.1038/s41467-020-20454-z]
Related Books
In Vitro Propagation and Secondary Metabolite Production from Medicinal Plants: Current Trends (Part 2)
Micropropagation of Medicinal Plants
Software and Programming Tools in Pharmaceutical Research
Biotechnology and Drug Development for Targeting Human Diseases
In Vitro Propagation and Secondary Metabolite Production from Medicinal Plants: Current Trends (Part 1)
Molecular and Physiological Insights into Plant Stress Tolerance and Applications in Agriculture- Part 2
Micropropagation of Medicinal Plants
Genome Editing in Bacteria (Part 1)
Data Science for Agricultural Innovation and Productivity
Animal Models In Experimental Medicine
Article Metrics
31
2