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Effects of PCSK9 missense variants on molecular conformation and biological activity in transfected HEK293FT cells
Los, Bruna; Ferreira, Glaucio Monteiro; Borges, Jéssica Bassani; Kronenberger, Thales; Oliveira, Victor Fernandes de; Dagli-Hernandez, Carolina; Bortolin, Raul Hernandes; Gonçalves, Rodrigo Marques; Faludi, Andre Arpad; Mori, Augusto Akira; Barbosa, Thais Kristini Almendros; Freitas, Renata Caroline Costa de; Jannes, Cinthia Elim; Pereira, Alexandre da Costa; Bastos, Gisele Medeiros; Poso, Antti; Hirata, Rosario Dominguez Crespo; Hirata, Mario Hiroyuki.
Afiliação
  • Los, Bruna; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo. São Paulo. BR
  • Ferreira, Glaucio Monteiro; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo. Laboratory of Molecular Research in Cardiology, Institute Dante Pazzanese of Cardiology. Department of Internal Medicine VIII, University Hospitals Tübingen. São Paulo. BR
  • Borges, Jéssica Bassani; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo. Laboratory of Molecular Research in Cardiology, Institute Dante Pazzanese of Cardiology. São Paulo. BR
  • Kronenberger, Thales; Department of Internal Medicine VIII, University Hospitals Tübingen. Tübingen. DE
  • Oliveira, Victor Fernandes de; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo. São Paulo. BR
  • Dagli-Hernandez, Carolina; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo. São Paulo. BR
  • Bortolin, Raul Hernandes; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo. Department of Cardiology, Boston Children's Hospital. São Paulo. BR
  • Gonçalves, Rodrigo Marques; Medical Clinic Division, Institute Dante Pazzanese of Cardiology. São Paulo. BR
  • Faludi, Andre Arpad; Medical Clinic Division, Institute Dante Pazzanese of Cardiology. São Paulo. BR
  • Mori, Augusto Akira; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo. São Paulo. BR
  • Barbosa, Thais Kristini Almendros; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo. São Paulo. BR
  • Freitas, Renata Caroline Costa de; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo. Department of Cardiac Surgery, Boston Children's Hospital. São Paulo. BR
  • Jannes, Cinthia Elim; Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo. São Paulo. BR
  • Pereira, Alexandre da Costa; Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo. São Paulo. BR
  • Bastos, Gisele Medeiros; Laboratory of Molecular Research in Cardiology, Institute Dante Pazzanese of Cardiology. Department of Teaching and Research, Real e Benemerita Associação Portuguesa de Beneficiência. São Paulo. BR
  • Poso, Antti; Department of Internal Medicine VIII, University Hospitals Tübingen. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland. Tübingen. DE
  • Hirata, Rosario Dominguez Crespo; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo. São Paulo. BR
  • Hirata, Mario Hiroyuki; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo. São Paulo. BR
Gene ; 851(146979)Oct. 2022.
Artigo em Inglês | CONASS, Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1400683
Biblioteca responsável: BR79.1
ABSTRACT
ABSTRACT PCSK9 gain-of-function (GOF) variants increase degradation of low-density lipoprotein receptor (LDLR) and are potentially associated with Familial Hypercholesterolemia (FH). This study aimed to explore the effects of PCSK9 missense variants on protein structure and interactions with LDLR using molecular modeling analyses and in vitro functional studies. Variants in FH-related genes were identified in a Brazilian FH cohort using an exon-target gene sequencing strategy. Eight PCSK9 missense variants in pro- [p.(E32K) and p.(E57K)], catalytic [p.(R237W), p.(P279T) and p.(A443T)], and C-terminal histidine-cysteine rich (CHR) [p.(R469W), p.(Q619P) and p.(R680Q)] domains were identified. Molecular dynamics analyses revealed that GOF variants p.(E32K) and p.(R469W) increased extreme motions in PCSK9 amino acid backbone fluctuations and affected Hbond and water bridge interactions between the pro-domain and CM1 region of the CHR domain. HEK293FT cells transfected with plasmids carrying p.(E32K) and p.(R469W) variants reduced LDLR expression (8.7 % and 14.8 %, respectively) compared to wild type (p < 0.05) but these GOF variants did not affect PCSK9 expression and secretion. The missense variants p.(P279T) and p.(Q619P) also reduced protein stability and altered Hbond interactions. In conclusion, PCSK9 p.(E32K), p.(R469W), p.(P279T) and p.(Q619P) variants disrupt intramolecular interactions that are essential for PCSK9 structural conformation and biological activity and may have a potential role in FH pathogenesis.
Assuntos
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Coleções: Bases de dados nacionais / Brasil Base de dados: CONASS / Sec. Est. Saúde SP / SESSP-IDPCPROD Assunto principal: Mutação de Sentido Incorreto / Hiperlipoproteinemia Tipo II / Conformação Molecular Limite: Humanos Idioma: Inglês Revista: Gene Ano de publicação: 2022 Tipo de documento: Artigo Instituição/País de afiliação: Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo/BR / Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo/BR / Department of Internal Medicine VIII, University Hospitals Tübingen/DE / Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo/BR / Laboratory of Molecular Research in Cardiology, Institute Dante Pazzanese of Cardiology/BR / Medical Clinic Division, Institute Dante Pazzanese of Cardiology/BR
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Coleções: Bases de dados nacionais / Brasil Base de dados: CONASS / Sec. Est. Saúde SP / SESSP-IDPCPROD Assunto principal: Mutação de Sentido Incorreto / Hiperlipoproteinemia Tipo II / Conformação Molecular Limite: Humanos Idioma: Inglês Revista: Gene Ano de publicação: 2022 Tipo de documento: Artigo Instituição/País de afiliação: Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo/BR / Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo/BR / Department of Internal Medicine VIII, University Hospitals Tübingen/DE / Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo/BR / Laboratory of Molecular Research in Cardiology, Institute Dante Pazzanese of Cardiology/BR / Medical Clinic Division, Institute Dante Pazzanese of Cardiology/BR
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