scholarly journals Elastic fibres in health and disease

2013 ◽  
Vol 15 ◽  
Author(s):  
Andrew K. Baldwin ◽  
Andreja Simpson ◽  
Ruth Steer ◽  
Stuart A. Cain ◽  
Cay M. Kielty
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Elastic Fibre ◽  
Cutis Laxa ◽  
Elastic Recoil ◽  
Elastic Fibres ◽  
Connective Tissues ◽  
Inflammatory Damage ◽  
Fibrillin 1 ◽  
Health And Disease

Elastic fibres are insoluble components of the extracellular matrix of dynamic connective tissues such as skin, arteries, lungs and ligaments. They are laid down during development, and comprise a cross-linked elastin core within a template of fibrillin-based microfibrils. Their function is to endow tissues with the property of elastic recoil, and they also regulate the bioavailability of transforming growth factor β. Severe heritable elastic fibre diseases are caused by mutations in elastic fibre components; for example, mutations in elastin cause supravalvular aortic stenosis and autosomal dominant cutis laxa, mutations in fibrillin-1 cause Marfan syndrome and Weill–Marchesani syndrome, and mutations in fibulins-4 and -5 cause autosomal recessive cutis laxa. Acquired elastic fibre defects include dermal elastosis, whereas inflammatory damage to fibres contributes to pathologies such as pulmonary emphysema and vascular disease. This review outlines the latest understanding of the composition and assembly of elastic fibres, and describes elastic fibre diseases and current therapeutic approaches.

scholarly journals Autosomal Recessive Cutis Laxa 1C Mutations Disrupt the Structure and Interactions of Latent TGFβ Binding Protein-4

2021 ◽  
Vol 12 ◽  
Author(s):  
Yasmene F. Alanazi ◽  
Michael P. Lockhart-Cairns ◽  
Stuart A. Cain ◽  
Thomas A. Jowitt ◽  
Anthony S. Weiss ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Binding Protein ◽  
Heparan Sulphate ◽  
Point Mutations ◽  
Elastic Fibre ◽  
Terminal Region ◽  
Cutis Laxa ◽  
Connective Tissues ◽  
Fibrillin 1 ◽  
Functional Consequences

Latent TGFβ binding protein-4 (LTBP4) is a multi-domain glycoprotein, essential for regulating the extracellular bioavailability of TGFβ and assembly of elastic fibre proteins, fibrillin-1 and tropoelastin. LTBP4 mutations are linked to autosomal recessive cutis laxa type 1C (ARCL1C), a rare congenital disease characterised by high mortality and severely disrupted connective tissues. Despite the importance of LTBP4, the structure and molecular consequences of disease mutations are unknown. Therefore, we analysed the structural and functional consequences of three ARCL1C causing point mutations which effect highly conserved cysteine residues. Our structural and biophysical data show that the LTBP4 N- and C-terminal regions are monomeric in solution and adopt extended conformations with the mutations resulting in subtle changes to their conformation. Similar to LTBP1, the N-terminal region is relatively inflexible, whereas the C-terminal region is flexible. Interaction studies show that one C-terminal mutation slightly decreases binding to fibrillin-1. We also found that the LTBP4 C-terminal region directly interacts with tropoelastin which is perturbed by both C-terminal ARCL1C mutations, whereas an N-terminal mutation increased binding to fibulin-4 but did not affect the interaction with heparan sulphate. Our results suggest that LTBP4 mutations contribute to ARCL1C by disrupting the structure and interactions of LTBP4 which are essential for elastogenesis in a range of mammalian connective tissues.

scholarly journals Kelch-like protein 42 is a profibrotic ubiquitin E3 ligase involved in systemic sclerosis

2020 ◽  
Vol 295 (13) ◽  
pp. 4171-4180 ◽  
Author(s):  
Travis B. Lear ◽  
Karina C. Lockwood ◽  
Mads Larsen ◽  
Ferhan Tuncer ◽  
Jason R. Kennerdell ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
E3 Ligase ◽  
Transforming Growth Factor Β ◽  
Lung Fibroblasts ◽  
Regulatory Subunit ◽  
Connective Tissues ◽  
E3 Ligases ◽  
Ubiquitin E3 Ligase

Systemic scleroderma (SSc) is an autoimmune disease that affects over 2.5 million people globally. SSc results in dysfunctional connective tissues with excessive profibrotic signaling, affecting skin, cardiovascular, and particularly lung tissue. Over three-quarters of individuals with SSc develop pulmonary fibrosis within 5 years, the main cause of SSc mortality. No approved medicines to manage lung SSc currently exist. Recent research suggests that profibrotic signaling by transforming growth factor β (TGF-β) is directly tied to SSc. Previous studies have also shown that ubiquitin E3 ligases potently control TGF-β signaling through targeted degradation of key regulatory proteins; however, the roles of these ligases in SSc–TGF-β signaling remain unclear. Here we utilized primary SSc patient lung cells for high-throughput screening of TGF-β signaling via high-content imaging of nuclear translocation of the profibrotic transcription factor SMAD family member 2/3 (SMAD2/3). We screened an RNAi library targeting ubiquitin E3 ligases and observed that knockdown of the E3 ligase Kelch-like protein 42 (KLHL42) impairs TGF-β–dependent profibrotic signaling. KLHL42 knockdown reduced fibrotic tissue production and decreased TGF-β–mediated SMAD activation. Using unbiased ubiquitin proteomics, we identified phosphatase 2 regulatory subunit B'ϵ (PPP2R5ϵ) as a KLHL42 substrate. Mechanistic experiments validated ubiquitin-mediated control of PPP2R5ϵ stability through KLHL42. PPP2R5ϵ knockdown exacerbated TGF-β–mediated profibrotic signaling, indicating a role of PPP2R5ϵ in SSc. Our findings indicate that the KLHL42–PPP2R5ϵ axis controls profibrotic signaling in SSc lung fibroblasts. We propose that future studies could investigate whether chemical inhibition of KLHL42 may ameliorate profibrotic signaling in SSc.

scholarly journals Induction and Coexpression of Latent Transforming Growth Factor β-Binding Protein-1 and Fibrillin-1 in Experimental Glomerulonephritis

2005 ◽  
Vol 102 (3-4) ◽  
pp. e99-e104 ◽  
Author(s):  
Markus Porst ◽  
Christoph Daniel ◽  
Christian Plank ◽  
Harald O. Schocklmann ◽  
Dieter P. Reinhardt ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Transforming Growth Factor Β ◽  
Experimental Glomerulonephritis ◽  
Fibrillin 1

New insights into the structure, assembly and biological roles of 10–12 nm connective tissue microfibrils from fibrillin-1 studies

2016 ◽  
Vol 473 (7) ◽  
pp. 827-838 ◽  
Author(s):  
Sacha A. Jensen ◽  
Penny A. Handford
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Transforming Growth Factor Β ◽  
Calcium Dependent ◽  
Matrix Interactions ◽  
Fibrillin 1 ◽  
Regulatory Effects ◽  
Cell Matrix Interactions ◽  
Structure Assembly

The 10–12 nm diameter microfibrils of the extracellular matrix (ECM) impart both structural and regulatory properties to load-bearing connective tissues. The main protein component is the calcium-dependent glycoprotein fibrillin, which assembles into microfibrils at the cell surface in a highly regulated process involving specific proteolysis, multimerization and glycosaminoglycan interactions. In higher metazoans, microfibrils act as a framework for elastin deposition and modification, resulting in the formation of elastic fibres, but they can also occur in elastin-free tissues where they perform structural roles. Fibrillin microfibrils are further engaged in a number of cell matrix interactions such as with integrins, bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β (TGFβ). Fibrillin-1 (FBN1) mutations are associated with a range of heritable connective disorders, including Marfan syndrome (MFS) and the acromelic dysplasias, suggesting that the roles of 10–12 nm diameter microfibrils are pleiotropic. In recent years the use of molecular, cellular and whole-organism studies has revealed that the microfibril is not just a structural component of the ECM, but through its network of cell and matrix interactions it can exert profound regulatory effects on cell function. In this review we assess what is known about the molecular properties of fibrillin that enable it to assemble into the 10–12 nm diameter microfibril and perform such diverse roles.

scholarly journals Identification of a Novel 19-bp Deletion Mutation in LTBP4 Using Exome Sequencing in Two Siblings with Autosomal Recessive Cutis Laxa Type 1C

2019 ◽  
Vol 09 (02) ◽  
pp. 125-131 ◽  
Author(s):  
Neerja Gupta ◽  
Nitika Langeh ◽  
Aparajit Sridharan ◽  
Madhulika Kabra
Keyword(s):  
Base Pair ◽  
Autosomal Recessive ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Homozygous Deletion ◽  
Cutis Laxa ◽  
Type I ◽  
Recessive Type ◽  
Single Base Pair ◽  
Biallelic Mutations

AbstractAutosomal recessive type I cutis laxa is genetically heterogeneous. Biallelic mutations in latent transforming growth factor β-binding protein 4 (LTBP4; MIM*604710) lead to type 1C cutis laxa due to nonsense, frameshift, single base pair indels, or duplication mutations. In this report, we describe the first Indian family with cutis laxa as a result of a novel 19 base pair homozygous deletion leading to premature termination of short isoform LTBP-4S.

scholarly journals O-Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations

2020 ◽  
Vol 295 (46) ◽  
pp. 15742-15753
Author(s):  
Ao Zhang ◽  
Steven J. Berardinelli ◽  
Christina Leonhard-Melief ◽  
Deepika Vasudevan ◽  
Ta-Wei Liu ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Consensus Sequence ◽  
Transforming Growth Factor Β ◽  
Connective Tissue Disorder ◽  
Matricellular Protein ◽  
Consensus Sequences ◽  
Skeletal Defects ◽  
Fibrillin 1 ◽  
Small Hands ◽  
Hands And Feet

ADAMTSL2 mutations cause an autosomal recessive connective tissue disorder, geleophysic dysplasia 1 (GPHYSD1), which is characterized by short stature, small hands and feet, and cardiac defects. ADAMTSL2 is a matricellular protein previously shown to interact with latent transforming growth factor-β binding protein 1 and influence assembly of fibrillin 1 microfibrils. ADAMTSL2 contains seven thrombospondin type-1 repeats (TSRs), six of which contain the consensus sequence for O-fucosylation by protein O-fucosyltransferase 2 (POFUT2). O-fucose–modified TSRs are subsequently elongated to a glucose β1-3-fucose (GlcFuc) disaccharide by β1,3-glucosyltransferase (B3GLCT). B3GLCT mutations cause Peters Plus Syndrome (PTRPLS), which is characterized by skeletal defects similar to GPHYSD1. Several ADAMTSL2 TSRs also have consensus sequences for C-mannosylation. Six reported GPHYSD1 mutations occur within the TSRs and two lie near O-fucosylation sites. To investigate the effects of TSR glycosylation on ADAMTSL2 function, we used MS to identify glycan modifications at predicted consensus sequences on mouse ADAMTSL2. We found that most TSRs were modified with the GlcFuc disaccharide at high stoichiometry at O-fucosylation sites and variable mannose stoichiometry at C-mannosylation sites. Loss of ADAMTSL2 secretion in POFUT2−/− but not in B3GLCT−/− cells suggested that impaired ADAMTSL2 secretion is not responsible for skeletal defects in PTRPLS patients. In contrast, secretion was significantly reduced for ADAMTSL2 carrying GPHYSD1 mutations (S641L in TSR3 and G817R in TSR6), and S641L eliminated O-fucosylation of TSR3. These results provide evidence that abnormalities in GPHYSD1 patients with this mutation are caused by loss of O-fucosylation on TSR3 and impaired ADAMTSL2 secretion.

Isolation of rat fibrillin-1 cDNA and its relevance in metanephric development

1998 ◽  
Vol 275 (5) ◽  
pp. F710-F723 ◽  
Author(s):  
Yashpal S. Kanwar ◽  
Kosuke Ota ◽  
Qiwei Yang ◽  
Anil Kumar ◽  
Jun Wada ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Transforming Growth Factor Β ◽  
Antisense Oligodeoxynucleotide ◽  
Metanephric Mesenchyme ◽  
Developmentally Regulated ◽  
Protein Motifs ◽  
Spatiotemporal Expression ◽  
Fibrillin 1

The role of fibrillin-1 in metanephrogenesis was investigated. Fibrillin-1 cDNA was isolated from the rat kidney cDNA library and sequenced, and its spatiotemporal expression was studied. It had ∼88% homology with human fibrillin-1 and had Ca2+ binding epidermal growth factor-like domains, transforming growth factor-β binding protein motifs, and an RGD binding site. Northern blot analysis revealed an ∼10-kb transcript, and fibrillin-1 expression was developmentally regulated. In situ hybridization and immunofluorescence studies indicated that at day 15 of gestation, fibrillin-1 is expressed in the metanephric mesenchyme. At day 18, its expression was confined to nascent blood vessels and glomeruli, and it increased in the newborn and neonatal kidneys. Immunoprecipitation revealed an ∼300-kDa band by SDS-PAGE. Treatment with fibrillin-1 antisense oligodeoxynucleotide induced marked dysmorphogenesis of the embryonic metanephroi. Concomitantly, the fibrillin-1 mRNA, antibody reactivity in the metanephroi, and fibrillin-1-specific radioincorporation were reduced. These data indicate that, like αvβ3integrin, a known morphogen and a putative receptor of fibrillin-1, the fibrillin-1 modulates events related to early organogenesis and possibly also the vascularization of the rat kidney.

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