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Tertiary structures of amyloidogenic and non-amyloidogenic transthyretin variants: new model for amyloid fibril formation.

Schormann N, Murrell JR, Benson MD
Amyloid 5 175-87 (1998)
Related entries: 1bzd, 1bze, 1tsh, 2trh, 2try

Cited: 24 times
EuropePMC logo PMID: 9818054

Abstract

The most common form of hereditary systemic amyloidosis is familial amyloidotic polyneuropathy associated with single amino acid changes in the plasma protein transthyretin. So far, high resolution structures of only three amyloidogenic variants (Met30, Ser84, Ile122) and one non-amyloidogenic variant (Thr109) have been reported complemented by X-ray fiber diffraction studies and image reconstruction from electron micrographs of amyloid fibrils. To investigate the role of structural factors in this disease, we extended our studies to other transthyretin variants. We report crystallization and structural investigations of three amyloidogenic (Arg10, Ala60, Tyr77) and two non-amyloidogenic variants (Ser6, Met119). The similarity of these structures to normal transthyretin does not give direct clues to the fibril forming process. Since transthyretin amyloid fibrils contain a major fragment starting at position 49, besides the intact molecule, we calculated the solvent accessibility of residue 48. Indeed, all amyloidogenic variants show an increased main chain solvent exposure when compared to normal transthyretin and non-amyloidogenic variants, which can be postulated to result in increased susceptibility to proteolysis. After limited proteolysis, dimers are incapable of reassociation to native tetramers. We present a model for amyloid fibril formation based on formation of fibrils from N-terminal truncated dimers as building blocks.

Reviews citing this publication (4)

  1. The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. Johnson SM, Connelly S, Fearns C, Powers ET, Kelly JW. J Mol Biol 421 185-203 (2012)
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  4. Modulation of the Mechanisms Driving Transthyretin Amyloidosis. Bezerra F, Saraiva MJ, Almeida MR. Front Mol Neurosci 13 592644 (2020)

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  14. Unfolding and aggregation of transthyretin by the truncation of 50 N-terminal amino acids. Mizuguchi M, Hayashi A, Takeuchi M, Dobashi M, Mori Y, Shinoda H, Aizawa T, Demura M, Kawano K. Proteins 72 261-269 (2008)
  15. Probing Medin Monomer Structure and its Amyloid Nucleation Using 13C-Direct Detection NMR in Combination with Structural Bioinformatics. Davies HA, Rigden DJ, Phelan MM, Madine J. Sci Rep 7 45224 (2017)
  16. In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis. Bezerra F, Niemietz C, Schmidt HHJ, Zibert A, Guo S, Monia BP, Gonçalves P, Saraiva MJ, Almeida MR. Int J Mol Sci 22 9488 (2021)
  17. Transthyretin Asn90 variant: amyloidogenic or non-amyloidogenic role. Bersano A, Del Bo R, Ballabio E, Cinnante C, Lanfranconi S, Comi GP, Baron P, Bresolin N, Candelise L. J Neurol Sci 284 113-115 (2009)
  18. Glycosylation of Serum Clusterin in Wild-Type Transthyretin-Associated (ATTRwt) Amyloidosis: A Study of Disease-Associated Compositional Features Using Mass Spectrometry Analyses. Torres-Arancivia CM, Chang D, Hackett WE, Zaia J, Connors LH. Biochemistry 59 4367-4378 (2020)
  19. Models for binding cooperativities of inhibitors with transthyretin. Wang H, Tang Y, Lei M. Arch Biochem Biophys 466 85-97 (2007)
  20. New TEMPO-Appended 2,2'-Bipyridine-Based Eu(III), Tb(III), Gd(III) and Sm(III) Complexes: Synthesis, Photophysical Studies and Testing Photoluminescence-Based Bioimaging Abilities. Slovesnova NV, Minin AS, Belousova AV, Ustyugov AA, Chaprov KD, Krinochkin AP, Valieva MI, Shtaitz YK, Starnovskaya ES, Nikonov IL, Tsmokalyuk AN, Kim GA, Santra S, Kopchuk DS, Nosova EV, Zyryanov GV. Molecules 27 8414 (2022)


Related citations provided by authors (1)

  1. Tertiary Structure of an Amyloid Immunoglobulin Light Chain Protein: A Proposed Model for Amyloid Fibril Formation. Schormann N, Murrell JR, Liepnieks JJ, Benson MD Proc. Natl. Acad. Sci. U.S.A. 92 9490-9494 (1995)

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