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Fibulin-4 Exerts a Dual Role in LTBP-4L–Mediated Matrix Assembly and Function

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Fibulin-4 Exerts a Dual Role in LTBP-4L–Mediated Matrix Assembly and Function Correction BIOCHEMISTRY Correction for “Fibulin-4 exerts a dual role in LTBP-4L–mediated matrix assembly and function,” by Heena Kumra, Valentin Nelea, Hana Hakami, Amelie Pagliuzza, Jelena Djokic, Jiongci Xu, Hiromi Yanagisawa, and Dieter P. Reinhardt, which was first published September 23, 2019; 10.1073/pnas.1901048116 (Proc. Natl. Acad. Sci. U.S.A. 116, 20428–20437). The authors note that an additional affiliation should be listed for Hana Hakami. The new affiliation should appear as Faculty of Sciences and Medical Studies, College of Sciences, Zoology Department, King Saud University, Riyadh 12372, Saudi Arabia. The corrected author and affiliation lines appear below. The online version has been corrected. The authors also note that the following statement should be added to the Acknowledgments: “H.H. received funding from the King Saud University and the Ottawa Cultural Bureau, Royal Embassy of Saudi Arabia.” Heena Kumraa, Valentin Neleaa,b, Hana Hakamia,c, Amelie Pagliuzzaa, Jelena Djokica, Jiongci Xua, Hiromi Yanagisawad, and Dieter P. Reinhardta,b CORRECTION aFaculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada; bFaculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada; cFaculty of Sciences and Medical Studies, College of Sciences, Zoology Department, King Saud University, Riyadh 12372, Saudi Arabia; and dLife Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, 305-8577 Tsukuba, Japan Published under the PNAS license. First published December 16, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1920843117 www.pnas.org PNAS | December 26, 2019 | vol. 116 | no. 52 | 27159 Downloaded by guest on September 27, 2021 Fibulin-4 exerts a dual role in LTBP-4L–mediated matrix assembly and function Heena Kumraa,1, Valentin Neleaa,b,1, Hana Hakamia,c, Amelie Pagliuzzaa, Jelena Djokica, Jiongci Xua, Hiromi Yanagisawad, and Dieter P. Reinhardta,b,2 aFaculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada; bFaculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada; cFaculty of Sciences and Medical Studies, College of Sciences, Zoology Department, King Saud University, Riyadh 12372, Saudi Arabia; and dLife Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, 305-8577 Tsukuba, Japan Edited by Andrea Heinz, University of Copenhagen, Copenhagen, Denmark, and accepted by Editorial Board Member F. Ulrich Hartl August 30, 2019 (received for review January 23, 2019) Elastogenesis is a hierarchical process by which cells form func- factor-like (cbEGF) domains and a C-terminal fibulin domain tional elastic fibers, providing elasticity and the ability to regulate (1). Fibulin-4 multimerizes into a disk-shaped particle with an growth factor bioavailability in tissues, including blood vessels, estimated 10 molecules (15). LTBP-4, a member of the LTBP lung, and skin. This process requires accessory proteins, including family, shares structural homology with fibrillins, both charac- fibulin-4 and -5, and latent TGF binding protein (LTBP)-4. Our data terized by extended cbEGF repeats interspersed with 8-cysteine demonstrate mechanisms in elastogenesis, focusing on the in- (TB and hybrid) domains. Based on the domain composition and teraction and functional interdependence between fibulin-4 and distribution, LTBP-4 is expected to adopt an extended structure, LTBP-4L and its impact on matrix deposition and function. We facilitating the linear deposition of tropoelastin onto microfibrils show that LTBP-4L is not secreted in the expected extended (11, 16–20). LTBP-4 exists in 2 major N-terminally distinct iso- structure based on its domain composition, but instead adopts a forms, the short (LTBP-4S) and the long (LTBP-4L), due to the compact conformation. Interaction with fibulin-4 surprisingly in- usage of different promoters (21, 22). In humans, mutations in duced a conformational switch from the compact to an elongated either fibulin-4, fibulin-5, or LTBP-4 result in autosomal re- LTBP-4L structure. This conversion was only induced by fibulin-4 cessive cutis laxa (ARCL) type 1B, 1A, and 1C, respectively, multimers associated with increased avidity for LTBP-4L; fibulin-4 characterized by inelastic skin and pulmonary emphysema monomers were inactive. The fibulin-4–induced conformational common to all types, and aortic tortuosity and aneurysm only change caused functional consequences in LTBP-4L in terms of caused by fibulin-4 mutations (23). A functional link has been established between LTBP-4L and fibulin-4 and between LTBP-4S binding to other elastogenic proteins, including fibronectin and and fibulin-5 using mouse models and cell culture studies (11, 20, fibrillin-1, and of LTBP-4L assembly. A transient exposure of 24). Fibulin-4 depends on LTBP-4L for its assembly/deposition (25). −/− LTBP-4L with fibulin-4 was sufficient to stably induce conforma- A reduced interaction of LTBP-4L with fibulin-4 in Ltbp4S ; R/R tional and functional changes; a stable complex was not required. Fbln4 mice results in impaired elastogenesis (24). However, −/− −/− These data define fibulin-4 as a molecular extracellular chaperone elastogenesis in Ltbp4S ;Fbln5 double-knockout mice was im- − − for LTBP-4L. The altered LTBP-4L conformation also promoted elas- proved as compared to Ltbp4S / mice (20). Despite some known togenesis, but only in the presence of fibulin-4, which is required functional relationships between the elastogenic proteins, the un- to escort tropoelastin onto the extended LTBP-4L molecule. Alto- derlying molecular mechanisms that drive hierarchical elastin as- gether, this study provides a dual mechanism for fibulin-4 in 1) sembly are largely elusive. inducing a stable conformational and functional change in LTBP- 4L, and 2) promoting deposition of tropoelastin onto the elongated Significance LTBP-4L. Soft tissues such as blood vessels, lung, and skin require vari- fibulin-4 | LTBP-4 | fibronectin | fibrillin-1 | elastic fibers ous extracellular proteins, including tropoelastin, fibrillins, fibulin-4, and latent TGF-β binding protein-4 (LTBP-4) to syn- lastogenesis is a highly hierarchical multistep molecular thesize functional elastic fibers in a highly hierarchical fashion. Eprocess by which cells form functional elastic fibers, pro- Mutations in these proteins cause heritable diseases, resulting viding elasticity to various soft tissues, including blood vessels, in deficient elastic fibers and function. We provide evidence for lung, and skin (1). This process begins with the secretion of fi- a dual role of fibulin-4 in this context. Our results demonstrate bronectin and its organization into a network, which acts as an how physical interactions between these elastogenic proteins organizer for the assembly of fibrillin-1 into microfibrils, as well play key roles in inducing conformational and functional as for the deposition of latent TGF-β binding protein (LTBP)-4, changes, which then impacts self-assembly and elastic fiber and fibulin-4 (2–6). The fibronectin network is not only required formation. This fundamental finding is essential to understand for the initiation of fibrillin-1 assembly, but is also essential for the pathogenesis of diseases associated with mutations in microfibril homoeostasis during early stages of matrix assembly elastogenic proteins. (7). Tropoelastin, the soluble precursor of mature elastin, forms microaggregates on the cell surface, which are deposited onto Author contributions: H.K., V.N., and D.P.R. designed research; H.K., V.N., H.H., A.P., J.D., microfibrils (8, 9). Elastic fiber formation requires several ac- and J.X. performed research; H.H. and H.Y. contributed new reagents/analytic tools; H.K., cessory proteins, including fibulin-4, fibulin-5, and LTBP-4 (10, V.N., and D.P.R. analyzed data; and H.K., V.N., and D.P.R. wrote the paper. 11). Fibulin-4 tethers lysyl oxidase and fibulin-5 lysyl oxidase like The authors declare no conflict of interest. 1 to tropoelastin, facilitating cross-links required for the forma- This article is a PNAS Direct Submission. A.H. is a guest editor invited by the tion of nascent elastic fibers (12–14). LTBP-4S indirectly binds to Editorial Board. tropoelastin via fibulin-5 and supports the linear deposition of Published under the PNAS license. fibulin-5, which in turn promotes elastic fiber formation (11). 1H.K. and V.N. contributed equally to this work. Here we report critical mechanistic roles of fibulin-4 and LTBP- 2To whom correspondence may be addressed. Email: [email protected]. 4L in the hierarchical elastin assembly process. This article contains supporting information online at https://www.pnas.org/lookup/suppl/ Fibulin-4 and -5 are members of the fibulin family character- doi:10.1073/pnas.1901048116/-/DCSupplemental. ized by tandem repeats of calcium binding epidermal growth First published September 23, 2019. 20428–20437 | PNAS | October 8, 2019 | vol. 116 | no. 41 www.pnas.org/cgi/doi/10.1073/pnas.1901048116 In this study we analyze the molecular interaction between we determined by SPR that fibulin-4 can indeed directly interact fibulin-4 and LTBP-4L and its structural consequence. We deter- with fibronectin with a KD = 177 ± 48 nM (Fig. 2A). The mine the functional relationship of fibulin-4 and LTBP-4L with the 2 proteins also completely colocalized in the extracellular matrix central elastogenic proteins fibronectin, fibrillin-1, and tropoelastin produced by dermal fibroblasts (Fig. 2B). Fibronectin interaction and define the significance of these interactions on matrix assembly sites on fibulin-4 were mapped to the central (cbEGF2-5; KD = and function. Employing a series of biophysical, cell culture, and in 12.6 ± 2.1 nM) and the C-terminal (cbEGF6-Cterm; KD = 13.5 ± vivo approaches, we show that fibulin-4 has a dual role in respect to 2.7 nM) regions of fibulin-4 (Fig. 2C). We further examined the LTBP-4L, first triggering structural changes and functional activa- contribution of fibulin-4 monomers, dimers, and multimers in tion of LTBP-4L, and then transporting tropoelastin onto fibrillin- fibronectin interaction.
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