Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Protein and Peptide Letters
  4. Fast Track Articles
  5. Fast Track Article
image of Identifying the Role of Individual Seal IAPP Amino Acids in Inhibiting the Aggregation of Human IAPP

Abstract

Introduction

The progression of type 2 diabetes in humans appears to be linked to the loss of insulin-producing β-cells. One of the major contributors to β-cell loss is the formation of toxic human IAPP amyloid (hIAPP, Islet Amyloid Polypeptide, amylin) in the pancreas. Inhibiting the formation of toxic hIAPP amyloid could slow, if not prevent altogether, the progression of type 2 diabetes. Many non-human organisms also express amyloidogenic IAPP variants known to kill pancreatic cells and give rise to diabetes-like symptoms. Surprisingly, some of these non-human IAPP variants function as inhibitors of hIAPP aggregation, raising the possibility of developing non-human IAPP peptides into anti-diabetic therapeutic peptides. One such inhibitory IAPP variant is seal IAPP, which has been shown to inhibit hIAPP aggregation. Seal IAPP only differs from hIAPP by three amino acids. In this study, each of the six seal/human IAPP permutations was analyzed to identify the role of each of the three amino acid positions in inhibiting hIAPP aggregation.

Aims

This study aimed to identify the minimal amino acid substitutions to yield a peptide inhibitor of human IAPP aggregation.

Objective

The goal of the study was to determine the minimal amino acid substitutions necessary to convert human IAPP into an amyloid-inhibiting peptide.

Methods

The formation of toxic hIAPP amyloid was monitored using Thioflavin T binding assays, atomic force microscopy, and MTT cell rescue studies.

Results

One seal IAPP variant retained amyloid-inhibition activity, and two variants appeared to be more amyloidogenic and toxic than wild-type human IAPP.

Conclusion

These results suggest that inhibition of hIAPP requires both the H18R and F23L substitutions of hIAPP.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ppl/10.2174/0109298665340227241115110404
2024-12-10
2025-01-31

  • From This Site

    /content/journals/ppl/10.2174/0109298665340227241115110404
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Kahn S.E. Clinical review 135: The importance of beta-cell failure in the development and progression of type 2 diabetes. J. Clin. Endocrinol. Metab. 2001 86 9 4047 4058 11549624
    [Google Scholar]
  2. 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 10.2337/diabetes.48.2.241 10334297
    [Google Scholar]
  3. Andrews M.E. Inayathullah N.M. Jayakumar R. Malar E.J.P. Conformational polymorphism and cellular toxicity of IAPP and βAP domains. J. Struct. Biol. 2009 166 2 116 125 10.1016/j.jsb.2008.12.011 19374013
    [Google Scholar]
  4. 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 s3 Suppl. 3 68 77 10.1111/j.1463‑1326.2012.01657.x 22928566
    [Google Scholar]
  5. Westermark P. Andersson A. Westermark G.T. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol. Rev. 2011 91 3 795 826 10.1152/physrev.00042.2009 21742788
    [Google Scholar]
  6. Jaikaran E.T.A.S. Clark A. Islet amyloid and type 2 diabetes: from molecular misfolding to islet pathophysiology. Biochim. Biophys. Acta Mol. Basis Dis. 2001 1537 3 179 203 10.1016/S0925‑4439(01)00078‑3 11731221
    [Google Scholar]
  7. Haataja L. Gurlo T. Huang C.J. Butler P.C. Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocr. Rev. 2008 29 3 303 316 10.1210/er.2007‑0037 18314421
    [Google Scholar]
  8. 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 10.1210/jc.2004‑0405 15292279
    [Google Scholar]
  9. Elenbaas B.O.W. Kremsreiter S.M. Khemtemourian L. Killian J.A. Sinnige T. Fibril elongation by human islet amyloid polypeptide is the main event linking aggregation to membrane damage. BBA Advances 2023 3 100083 10.1016/j.bbadva.2023.100083 37082256
    [Google Scholar]
  10. Buchanan L.E. Dunkelberger E.B. Tran H.Q. Cheng P.N. Chiu C.C. Cao P. Raleigh D.P. de Pablo J.J. Nowick J.S. Zanni M.T. Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet. Proc. Natl. Acad. Sci. USA 2013 110 48 19285 19290 10.1073/pnas.1314481110 24218609
    [Google Scholar]
  11. Röder C. Kupreichyk T. Gremer L. Schäfer L.U. Pothula K.R. Ravelli R.B.G. Willbold D. Hoyer W. Schröder G.F. Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils. Nat. Struct. Mol. Biol. 2020 27 7 660 667 10.1038/s41594‑020‑0442‑4 32541895
    [Google Scholar]
  12. Liu C. Zhao M. Jiang L. Cheng P.N. Park J. Sawaya M.R. Pensalfini A. Gou D. Berk A.J. Glabe C.G. Nowick J. Eisenberg D. Out-of-register β-sheets suggest a pathway to toxic amyloid aggregates. Proc. Natl. Acad. Sci. USA 2012 109 51 20913 20918 10.1073/pnas.1218792109 23213214
    [Google Scholar]
  13. Laganowsky A. Liu C. Sawaya M.R. Whitelegge J.P. Park J. Zhao M. Pensalfini A. Soriaga A.B. Landau M. Teng P.K. Cascio D. Glabe C. Eisenberg D. Atomic view of a toxic amyloid small oligomer. Science 2012 335 6073 1228 1231 10.1126/science.1213151 22403391
    [Google Scholar]
  14. Rodriguez Camargo D.C. Korshavn K.J. Jussupow A. Raltchev K. Goricanec D. Fleisch M. Sarkar R. Xue K. Aichler M. Mettenleiter G. Walch A.K. Camilloni C. Hagn F. Reif B. Ramamoorthy A. Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate. eLife 2017 6 e31226 10.7554/eLife.31226 29148426
    [Google Scholar]
  15. Schlamadinger D.E. Miranker A.D. Fiber-dependent and -independent toxicity of islet amyloid polypeptide. Biophys. J. 2014 107 11 2559 2566 10.1016/j.bpj.2014.09.047 25468335
    [Google Scholar]
  16. Bram Y. Frydman-Marom A. Yanai I. Gilead S. Shaltiel-Karyo R. Amdursky N. Gazit E. Apoptosis induced by islet amyloid polypeptide soluble oligomers is neutralized by diabetes-associated specific antibodies. Sci Rep 2014 2014
    [Google Scholar]
  17. Cao Q. Boyer D.R. Sawaya M.R. Abskharon R. Saelices L. Nguyen B.A. Lu J. Murray K.A. Kandeel F. Eisenberg D.S. Cryo-EM structures of hIAPP fibrils seeded by patient-extracted fibrils reveal new polymorphs and conserved fibril cores. Nat. Struct. Mol. Biol. 2021 28 9 724 730 10.1038/s41594‑021‑00646‑x 34518699
    [Google Scholar]
  18. DeToma A.S. Salamekh S. Ramamoorthy A. Lim M.H. Misfolded proteins in Alzheimer’s disease and type II diabetes. Chem. Soc. Rev. 2012 41 2 608 621 10.1039/C1CS15112F 21818468
    [Google Scholar]
  19. Cox S.J. Rodriguez Camargo D.C. Lee Y.H. Dubini R.C.A. Rovó P. Ivanova M.I. Padmini V. Reif B. Ramamoorthy A. Small molecule induced toxic human-IAPP species characterized by NMR. Chem. Commun. (Camb.) 2020 56 86 13129 13132 10.1039/D0CC04803H 33006345
    [Google Scholar]
  20. Marmentini C. Branco R.C.S. Boschero A.C. Kurauti M.A. Islet amyloid toxicity: From genesis to counteracting mechanisms. J. Cell. Physiol. 2022 237 2 1119 1142 10.1002/jcp.30600 34636428
    [Google Scholar]
  21. Ritzel R.A. Meier J.J. Lin C.Y. Veldhuis J.D. Butler P.C. Human islet amyloid polypeptide oligomers disrupt cell coupling, induce apoptosis, and impair insulin secretion in isolated human islets. Diabetes 2007 56 1 65 71 10.2337/db06‑0734 17192466
    [Google Scholar]
  22. Yan L.M. Velkova A. Tatarek-Nossol M. Andreetto E. Kapurniotu A. IAPP mimic blocks Abeta cytotoxic self-assembly: cross-suppression of amyloid toxicity of Abeta and IAPP suggests a molecular link between Alzheimer’s disease and type II diabetes. Angew. Chem. Int. Ed. 2007 46 8 1246 1252 10.1002/anie.200604056 17203498
    [Google Scholar]
  23. Kapurniotu A. Schmauder A. Tenidis K. Structure-based design and study of non-amyloidogenic, double N-methylated IAPP amyloid core sequences as inhibitors of IAPP amyloid formation and cytotoxicity. J. Mol. Biol. 2002 315 3 339 350 10.1006/jmbi.2001.5244 11786016
    [Google Scholar]
  24. Kayed R. Head E. Thompson J.L. McIntire T.M. Milton S.C. Cotman C.W. Glabe C.G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003 300 5618 486 489 10.1126/science.1079469 12702875
    [Google Scholar]
  25. Wakabayashi M. Matsuzaki K. Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts. FEBS Lett. 2009 583 17 2854 2858 10.1016/j.febslet.2009.07.044 19647738
    [Google Scholar]
  26. 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 10.3109/13506129.2015.1070824 26300107
    [Google Scholar]
  27. 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 10.1002/psc.3199 31231935
    [Google Scholar]
  28. Westermark P. Engström U. Johnson K.H. Westermark G.T. Betsholtz C. Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc. Natl. Acad. Sci. USA 1990 87 13 5036 5040 10.1073/pnas.87.13.5036 2195544
    [Google Scholar]
  29. Berhanu W.M. Hansmann U.H.E. Inter-species cross-seeding: stability and assembly of rat-human amylin aggregates. PLoS One 2014 9 5 e97051 10.1371/journal.pone.0097051 24810618
    [Google Scholar]
  30. Oakes A. Menefee K. Lamba A. Palato L.M. Rinauro D.J. Tun A. Jauregui B. Chang K. Nogaj L.A. Moffet D.A. Nonhuman IAPP Variants Inhibit Human IAPP Aggregation. Protein Pept. Lett. 2021 28 9 963 971 10.2174/0929866528666210806152706 34365921
    [Google Scholar]
  31. Sanders H.M. Chalyavi F. Fields C.R. Kostelic M.M. Li M.H. Raleigh D.P. Zanni M.T. Marty M.T. Interspecies Variation Affects Islet Amyloid Polypeptide Membrane Binding. J. Am. Soc. Mass Spectrom. 2023 34 6 986 990 10.1021/jasms.3c00005 37126782
    [Google Scholar]
  32. Fox A. Snollaerts T. Errecart Casanova C. Calciano A. Nogaj L.A. Moffet D.A. Selection for nonamyloidogenic mutants of islet amyloid polypeptide (IAPP) identifies an extended region for amyloidogenicity. Biochemistry 2010 49 36 7783 7789 10.1021/bi100337p 20698575
    [Google Scholar]
  33. Fuentes A.L. Hennessy K. Pascual J. Pepe N. Wang I. Santiago A. Chaggan C. Martinez J. Rivera E. Cota P. Cunha C. Nogaj L.A. Moffet D.A. Identification of plant extracts that inhibit the formation of diabetes-linked IAPP amyloid. J. Herb. Med. 2016 6 1 37 41 10.1016/j.hermed.2015.11.001 27042401
    [Google Scholar]
  34. Levine H. III Thioflavine T interaction with synthetic Alzheimer’s disease β ‐amyloid peptides: Detection of amyloid aggregation in solution. Protein Sci. 1993 2 3 404 410 10.1002/pro.5560020312 8453378
    [Google Scholar]
  35. Wang S.T. Lin Y. Hsu C.C. Amdursky N. Spicer C.D. Stevens M.M. Probing amylin fibrillation at an early stage via a tetracysteine-recognising fluorophore. Talanta 2017 173 44 50 10.1016/j.talanta.2017.05.015 28602190
    [Google Scholar]
  36. Wong A.G. Wu C. Hannaberry E. Watson M.D. Shea J.E. Raleigh D.P. 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 10.1021/acs.biochem.5b01107 26694855
    [Google Scholar]
  37. Wang Z. Zhou C. Wang C. Wan L. Fang X. Bai C. AFM and STM study of β-amyloid aggregation on graphite. Ultramicroscopy 2003 97 1-4 73 79 10.1016/S0304‑3991(03)00031‑7 12801659
    [Google Scholar]
  38. Watanabe-Nakayama T. Sahoo B.R. Ramamoorthy A. Ono K. High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways. Int. J. Mol. Sci. 2020 21 12 4287 10.3390/ijms21124287 32560229
    [Google Scholar]
/content/journals/ppl/10.2174/0109298665340227241115110404
Loading
Identifying the Role of Individual Seal IAPP Amino Acids in Inhibiting the Aggregation of Human IAPP
Bentham Science Publishers ; https://doi.org/10.2174/0109298665340227241115110404
/content/journals/ppl/10.2174/0109298665340227241115110404
/content/journals/ppl/10.2174/0109298665340227241115110404
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: amylin ; IAPP ; Amyloid inhibition ; diabetes ; protein aggregation ; islet amyloid

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test