The Inhibition of Serum Amyloid A Protein Aggregation by a Five-Residue Peptidomimetic: Structural and Morphological Insights.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, c1995-
    • Subject Terms:
      Peptidomimetics*/chemistry ; Peptidomimetics*/pharmacology ; Serum Amyloid A Protein*/chemistry ; Serum Amyloid A Protein*/metabolism ; Protein Aggregates*/drug effects; Humans
    • Abstract:
      Serum amyloid A (SAA) is a small protein consisting of 104 residues and, under physiological conditions, exists mainly in hexameric form. It belongs to the positive acute-phase proteins, which means that its plasma concentration increases rapidly in response to injury, inflammation, and infection. The accumulation of SAA molecules promotes the formation of amyloid aggregates, which deposit extracellularly in many organs, causing their dysfunction. In our previous work, we successfully designed a peptidomimetic that inhibited the aggregation of amyloidogenic SAA fragments. In the present paper, we show how the same inhibitor, named saa3Dip, affects the oligomerization and aggregation processes of MetSAA1.1 protein. The thioflavin T assay showed that saa3Dip inhibited its fibrillization. The measurement of the internal fluorophore fluorescence (Trp) showed differences that occurred in the tertiary structure of MetSAA1.1 in the presence of the inhibitor, which was also confirmed by CD spectra in the aromatic range. FTIR results suggested that saa3Dip could stabilize some fragments of the native structure of MetSAA1.1, which was confirmed by determining the melting temperature (Tm) of the protein-inhibitor complex. AFM images demonstrated that the presence of saa3Dip prevented the formation of large SAA aggregates. Our results suggest that saa3Dip stabilizes the native conformation of MetSAA1.1.
      Competing Interests: The authors declare no conflict of interest.
    • References:
      Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5189-94. (PMID: 24706838)
      Arch Biochem Biophys. 2020 Mar 15;681:108264. (PMID: 31945312)
      FASEB J. 2002 Jan;16(1):77-83. (PMID: 11772939)
      Mol Neurodegener. 2023 Nov 9;18(1):80. (PMID: 37940962)
      Nat Commun. 2020 Jan 29;11(1):571. (PMID: 31996674)
      Protein Sci. 2006 Apr;15(4):862-70. (PMID: 16600970)
      Amino Acids. 2016 Apr;48(4):1069-1078. (PMID: 26759015)
      Nature. 2024 Jun;630(8016):493-500. (PMID: 38718835)
      Rheum Dis Clin North Am. 2018 Nov;44(4):585-603. (PMID: 30274625)
      J Biol Chem. 2013 Jan 25;288(4):2744-55. (PMID: 23223242)
      Cytokine Growth Factor Rev. 2021 Jun;59:71-83. (PMID: 33727011)
      Protein Sci. 2024 May;33(5):e4983. (PMID: 38659173)
      Curr Med Chem. 2016;23(17):1725-55. (PMID: 27087246)
      Amyloid. 2020 Mar;27(1):1-12. (PMID: 31766892)
      Cell Mol Life Sci. 2009 Jan;66(1):9-26. (PMID: 18726069)
      Amyloid. 2004 Jun;11(2):71-80. (PMID: 15478462)
      ACS Chem Neurosci. 2012 Dec 19;3(12):1008-16. (PMID: 23259036)
      Biochem Biophys Res Commun. 2004 Apr 23;317(1):157-61. (PMID: 15047161)
      PLoS One. 2013 Jun 04;8(6):e64974. (PMID: 23750222)
      Int J Mol Sci. 2013 Sep 05;14(9):18362-84. (PMID: 24013380)
      Amyloid. 2012 Mar;19(1):5-14. (PMID: 22320226)
      Sci Rep. 2018 Jan 29;8(1):1783. (PMID: 29379133)
      ACS Med Chem Lett. 2021 Oct 05;12(10):1613-1621. (PMID: 34676044)
      Lancet. 2001 Jul 7;358(9275):24-9. (PMID: 11454373)
      Annu Rev Pathol. 2015;10:321-44. (PMID: 25387054)
      Eur Heart J Cardiovasc Imaging. 2023 Mar 21;24(4):e59. (PMID: 36595341)
      J Biol Chem. 2002 Oct 4;277(40):36948-54. (PMID: 12149256)
      Biochemistry. 2008 Feb 19;47(7):1984-92. (PMID: 18189413)
      ACS Omega. 2021 Apr 22;6(17):11131-11138. (PMID: 34056268)
      Int J Biol Macromol. 2020 Aug 1;156:949-959. (PMID: 32199918)
      Nat Commun. 2024 Aug 17;15(1):7083. (PMID: 39153989)
      J Biol Chem. 2022 May;298(5):101902. (PMID: 35390347)
    • Grant Information:
      Diamond grant DI2015 022445 Ministry of Science and Higher Education
    • Contributed Indexing:
      Keywords: aggregation; inhibitor; serum amyloid A
    • Accession Number:
      0 (Peptidomimetics)
      0 (Serum Amyloid A Protein)
      0 (Protein Aggregates)
    • Publication Date:
      Date Created: 20241109 Date Completed: 20241109 Latest Revision: 20241116
    • Publication Date:
      20241116
    • Accession Number:
      PMC11547336
    • Accession Number:
      10.3390/molecules29215165
    • Accession Number:
      39519806