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Fibulin-4 exerts a dual role in LTBP-4L-mediated matrix assembly and function.
Kumra, Heena; Nelea, Valentin; Hakami, Hana; Pagliuzza, Amelie; Djokic, Jelena; Xu, Jiongci; Yanagisawa, Hiromi; Reinhardt, Dieter P.
Afiliação
  • Kumra H; Faculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada.
  • Nelea V; Faculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada.
  • Hakami H; Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada.
  • Pagliuzza A; Faculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada.
  • Djokic J; Faculty of Sciences and Medical Studies, College of Sciences, Zoology Department, King Saud University, Riyadh 12372, Saudi Arabia
  • Xu J; Faculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada.
  • Yanagisawa H; Faculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada.
  • Reinhardt DP; Faculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada.
Proc Natl Acad Sci U S A ; 116(41): 20428-20437, 2019 10 08.
Article em En | MEDLINE | ID: mdl-31548410
ABSTRACT
Elastogenesis is a hierarchical process by which cells form functional elastic fibers, providing elasticity and the ability to regulate growth factor bioavailability in tissues, including blood vessels, lung, and skin. This process requires accessory proteins, including fibulin-4 and -5, and latent TGF binding protein (LTBP)-4. Our data demonstrate mechanisms in elastogenesis, focusing on the interaction and functional interdependence between fibulin-4 and LTBP-4L and its impact on matrix deposition and function. We show that LTBP-4L is not secreted in the expected extended structure based on its domain composition, but instead adopts a compact conformation. Interaction with fibulin-4 surprisingly induced a conformational switch from the compact to an elongated LTBP-4L structure. This conversion was only induced by fibulin-4 multimers associated with increased avidity for LTBP-4L; fibulin-4 monomers were inactive. The fibulin-4-induced conformational change caused functional consequences in LTBP-4L in terms of binding to other elastogenic proteins, including fibronectin and fibrillin-1, and of LTBP-4L assembly. A transient exposure of LTBP-4L with fibulin-4 was sufficient to stably induce conformational and functional changes; a stable complex was not required. These data define fibulin-4 as a molecular extracellular chaperone for LTBP-4L. The altered LTBP-4L conformation also promoted elastogenesis, but only in the presence of fibulin-4, which is required to escort tropoelastin onto the extended LTBP-4L molecule. Altogether, this study provides a dual mechanism for fibulin-4 in 1) inducing a stable conformational and functional change in LTBP-4L, and 2) promoting deposition of tropoelastin onto the elongated LTBP-4L.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas da Matriz Extracelular / Proteínas de Ligação a TGF-beta Latente / Fibroblastos Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas da Matriz Extracelular / Proteínas de Ligação a TGF-beta Latente / Fibroblastos Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article