Fibrillin-containing microfibrils: Structure and function in health and disease
ABSTRACT Fibrillin-containing microfibrils are a unique class of connective tissue macromolecules whose critical contribution to the establishment and maintenance of diverse extracellular matrices was underlined by the recent linkage of their principal structural component fibrillin to Marfan syndrome, a heritable disorder with pleiotrophic connective tissue manifestations. The complexity of the structure: function relationships of these macromolecules was highlighted by the recent elucidation of the primary structure of fibrillin and characterisation of fibrillin mutations in Marfan patients. This review examines current understanding of the expression and assembly of fibrillin and describes new approaches which are now being applied to elucidate the many outstanding structural, organisational and functional aspects of the fibrillin-containing microfibrils.
- SourceAvailable from: Glenda Wright
[Show abstract] [Hide abstract]
- "Low calcium concentration may cause changes in the charge profile of molecules within the microfibrils. These changes would alter molecular interactions (Kielty and Shuttleworth, 1995). Downing et al. (1996) resolved the NMR structure of microfibrils, showing that there are in fact such interactions. "
ABSTRACT: Marfan syndrome, a connective tissue disorder affecting the cardiovascular system, is caused by mutations of fibrillin-based microfibrils. These mutations often affect the calcium-binding domains, resulting in structural changes to the proteins. It is hypothesized that these Ca+2 binding sites regulate the structure and mechanical properties of the microfibrils. The mechanical properties of fresh and extracted lobster aortic rings in calcium solutions (1, 13 and 30 mM Ca+2) were measured. Samples underwent amino acid compositional analysis. Antibodies were produced against the material comprising extracted aortic rings. The ultrastructure of strained and unstrained samples was examined using transmission electron microscopy. Calcium level altered the tangent modulus of fresh vessels. These rings were significantly stiffer when tested at 30 mM Ca+2 compared to rings tested at 1 mM Ca+2. Amino acid comparisons between extracted samples, porcine and human fibrillin showed compositional similarity. Immunohistochemical analysis showed that antibodies produced against the material in extracted samples localized to the known microfibrillar elements in the lobster aorta and cross-reacted with fibrillin microfibrils of mammalian ciliary zonules. Ultrastructurally, vessels incubated in low calcium solutions showed diffuse interbead regions while those incubated in physiological or high calcium solutions showed interbead regions with more defined lateral edges.Comparative Biochemistry and Physiology - Part A Molecular & Integrative Physiology 05/2006; 143(4):417-28. DOI:10.1016/j.cbpa.2005.09.020 · 2.37 Impact Factor
[Show abstract] [Hide abstract]
- "). FBN2 is responsible for congenital contractural arachnodactyly, which shares some of the physical features of Marfan syndrome caused by FBN1 mutation (Tsipouras et al. 1992). Fibrillin 1 and 2 are large cystein-rich glycoproteins that form microfibrils and that play a central role in elastic fibrogenesis (Kielty and Shuttleworth 1995; Robinson and Godfrey 2000). Lysyl oxidase, encoded by LOX, is an extracellular copper enzyme that initiates cross-linking processes by catalyzing oxidative deamination of epsilon-amino groups in certain lysine or hydroxylysine residues of collagens and lysine residues of elastin (Kagan et al. 1986; Kagan and Trackman 1991). "
ABSTRACT: We previously performed a genome-wide linkage study of intracranial aneurysm (IA) and found positive evidence of linkage at chromosomes 5q22-31, 7q11, and 14q22. In the present study, we focus on 5q31, where three candidate genes, fibroblast growth factor 1 (FGF1), fibrillin 2 (FBN2), and lysyl oxidase gene ( LOX) lie, and evaluate associations with IA. Genomic DNAs were obtained from 172 IA patients and 192 controls. Association analysis was performed with ten, five, and four single-nucleotide polymorphisms (SNPs) identified in FGF1, FBN2, and LOX, respectively. A difference in allelic frequency was observed for only the SNP at intron 4 in FGF1 (chi(2)=4.44, df=1, P=0.035). Although a haplotype association was observed with the combination of ten SNPs in FGF1 (chi(2)=16.04, df=1, P=0.00006), significant haplotype associations were not observed when haplotypes were constructed with the three, two, and four SNPs in FGF1 according to the linkage disequilibrium structure. No associations of FBN2 and LOX with IA were detected in the present study.Journal of Human Genetics 02/2003; 48(6):309-14. DOI:10.1007/s10038-003-0030-6 · 2.53 Impact Factor
[Show abstract] [Hide abstract]
- "Fibrillins form the structural framework of an essential class of extracellular microfibrils that endow dynamic connective tissues with long-range elasticity (Sakai et al., 1986; Kielty and Shuttleworth, 1995; Sherratt et al., 2001). Their importance is emphasized by linkage of fibrillin mutations to Marfan syndrome and related connective tissue disorders that are associated with severe cardiovascular, ocular, and skeletal defects (Robinson and Godfrey, 2000). "
ABSTRACT: We propose a new model for the alignment of fibrillin molecules within fibrillin microfibrils. Automated electron tomography was used to generate three-dimensional microfibril reconstructions to 18.6-A resolution, which revealed many new organizational details of untensioned microfibrils, including heart-shaped beads from which two arms emerge, and interbead diameter variation. Antibody epitope mapping of untensioned microfibrils revealed the juxtaposition of epitopes at the COOH terminus and near the proline-rich region, and of two internal epitopes that would be 42-nm apart in unfolded molecules, which infers intramolecular folding. Colloidal gold binds microfibrils in the absence of antibody. Comparison of colloidal gold and antibody binding sites in untensioned microfibrils and those extended in vitro, and immunofluorescence studies of fibrillin deposition in cell layers, indicate conformation changes and intramolecular folding. Mass mapping shows that, in solution, microfibrils with periodicities of <70 and >140 nm are stable, but periodicities of approximately 100 nm are rare. Microfibrils comprise two in-register filaments with a longitudinal symmetry axis, with eight fibrillin molecules in cross section. We present a model of fibrillin alignment that fits all the data and indicates that microfibril extensibility follows conformation-dependent maturation from an initial head-to-tail alignment to a stable approximately one-third staggered arrangement.The Journal of Cell Biology 04/2001; 152(5):1045-56. DOI:10.1083/jcb.152.5.1045 · 9.69 Impact Factor