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The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin: IMPLICATIONS FOR TRANSTHYRETIN-RELATED AMYLOIDOSES
Protein aggregation into β-sheet-enriched amyloid fibrils is associated with an increasing number of human disorders. The adoption of such amyloid conformations seems to constitute a generic property of polypeptide chains. Therefore, during evolution, proteins have adopted negative design strategies...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192486/ https://www.ncbi.nlm.nih.gov/pubmed/25086037 http://dx.doi.org/10.1074/jbc.M114.563981 |
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author | Sant'Anna, Ricardo Braga, Carolina Varejão, Nathalia Pimenta, Karinne M. Graña-Montes, Ricardo Alves, Aline Cortines, Juliana Cordeiro, Yraima Ventura, Salvador Foguel, Debora |
author_facet | Sant'Anna, Ricardo Braga, Carolina Varejão, Nathalia Pimenta, Karinne M. Graña-Montes, Ricardo Alves, Aline Cortines, Juliana Cordeiro, Yraima Ventura, Salvador Foguel, Debora |
author_sort | Sant'Anna, Ricardo |
collection | PubMed |
description | Protein aggregation into β-sheet-enriched amyloid fibrils is associated with an increasing number of human disorders. The adoption of such amyloid conformations seems to constitute a generic property of polypeptide chains. Therefore, during evolution, proteins have adopted negative design strategies to diminish their intrinsic propensity to aggregate, including enrichment of gatekeeper charged residues at the flanks of hydrophobic aggregation-prone segments. Wild type transthyretin (TTR) is responsible for senile systemic amyloidosis, and more than 100 mutations in the TTR gene are involved in familial amyloid polyneuropathy. The TTR 26–57 segment bears many of these aggressive amyloidogenic mutations as well as the binding site for heparin. We demonstrate here that Lys-35 acts as a gatekeeper residue in TTR, strongly decreasing its amyloidogenic potential. This protective effect is sequence-specific because Lys-48 does not affect TTR aggregation. Lys-35 is part of the TTR basic heparin-binding motif. This glycosaminoglycan blocks the protective effect of Lys-35, probably by neutralization of its side chain positive charge. A K35L mutation emulates this effect and results in the rapid self-assembly of the TTR 26–57 region into amyloid fibrils. This mutation does not affect the tetrameric protein stability, but it strongly increases its aggregation propensity. Overall, we illustrate how TTR is yet another amyloidogenic protein exploiting negative design to prevent its massive aggregation, and we show how blockage of conserved protective features by endogenous factors or mutations might result in increased disease susceptibility. |
format | Online Article Text |
id | pubmed-4192486 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-41924862014-10-10 The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin: IMPLICATIONS FOR TRANSTHYRETIN-RELATED AMYLOIDOSES Sant'Anna, Ricardo Braga, Carolina Varejão, Nathalia Pimenta, Karinne M. Graña-Montes, Ricardo Alves, Aline Cortines, Juliana Cordeiro, Yraima Ventura, Salvador Foguel, Debora J Biol Chem Molecular Bases of Disease Protein aggregation into β-sheet-enriched amyloid fibrils is associated with an increasing number of human disorders. The adoption of such amyloid conformations seems to constitute a generic property of polypeptide chains. Therefore, during evolution, proteins have adopted negative design strategies to diminish their intrinsic propensity to aggregate, including enrichment of gatekeeper charged residues at the flanks of hydrophobic aggregation-prone segments. Wild type transthyretin (TTR) is responsible for senile systemic amyloidosis, and more than 100 mutations in the TTR gene are involved in familial amyloid polyneuropathy. The TTR 26–57 segment bears many of these aggressive amyloidogenic mutations as well as the binding site for heparin. We demonstrate here that Lys-35 acts as a gatekeeper residue in TTR, strongly decreasing its amyloidogenic potential. This protective effect is sequence-specific because Lys-48 does not affect TTR aggregation. Lys-35 is part of the TTR basic heparin-binding motif. This glycosaminoglycan blocks the protective effect of Lys-35, probably by neutralization of its side chain positive charge. A K35L mutation emulates this effect and results in the rapid self-assembly of the TTR 26–57 region into amyloid fibrils. This mutation does not affect the tetrameric protein stability, but it strongly increases its aggregation propensity. Overall, we illustrate how TTR is yet another amyloidogenic protein exploiting negative design to prevent its massive aggregation, and we show how blockage of conserved protective features by endogenous factors or mutations might result in increased disease susceptibility. American Society for Biochemistry and Molecular Biology 2014-10-10 2014-08-01 /pmc/articles/PMC4192486/ /pubmed/25086037 http://dx.doi.org/10.1074/jbc.M114.563981 Text en © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/) applies to Author Choice Articles |
spellingShingle | Molecular Bases of Disease Sant'Anna, Ricardo Braga, Carolina Varejão, Nathalia Pimenta, Karinne M. Graña-Montes, Ricardo Alves, Aline Cortines, Juliana Cordeiro, Yraima Ventura, Salvador Foguel, Debora The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin: IMPLICATIONS FOR TRANSTHYRETIN-RELATED AMYLOIDOSES |
title | The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin: IMPLICATIONS FOR TRANSTHYRETIN-RELATED AMYLOIDOSES |
title_full | The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin: IMPLICATIONS FOR TRANSTHYRETIN-RELATED AMYLOIDOSES |
title_fullStr | The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin: IMPLICATIONS FOR TRANSTHYRETIN-RELATED AMYLOIDOSES |
title_full_unstemmed | The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin: IMPLICATIONS FOR TRANSTHYRETIN-RELATED AMYLOIDOSES |
title_short | The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin: IMPLICATIONS FOR TRANSTHYRETIN-RELATED AMYLOIDOSES |
title_sort | importance of a gatekeeper residue on the aggregation of transthyretin: implications for transthyretin-related amyloidoses |
topic | Molecular Bases of Disease |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192486/ https://www.ncbi.nlm.nih.gov/pubmed/25086037 http://dx.doi.org/10.1074/jbc.M114.563981 |
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