The International Journal of Biochemistry & Cell Biology
Molecules in focusThe fibrillins
Introduction
Fibrillins-1 and 2 are major structural components of the extracellular microfibrils with average diameter of 10 nm. Fibrillin-containing microfibrils are distributed in a wide variety of tissues and organs, either associated with elastin in the elastic fibers or as elastin-free bundles. Fibrillin-1 was first isolated in 1986 by Sakai et al.[1]from cultured fibroblasts using an antibody against tissue microfibrils. Fibrillin-2 was serendipitously discovered five years later by Lee et al.[2]during the cloning of the fibrillin-1 gene. Fibrillins are cysteine-rich glycoproteins made of structural motifs that are also found in other microfibril-interacting molecules, namely fibulins-1 and 2 and latent TGF-β-binding proteins-1 and 2 (LTBP-1 and LTBP-2). The bulk of fibrillin-1 synthesis correlates with late morphogenesis, whereas fibrillin-2 production peaks earlier and before overt elastogenesis[3]. Fibrillin-1 mutations cause the pleiotropic manifestations of Marfan syndrome (MFS); fibrillin-2 abnormalities result in the skeletal abnormalities of congenital contractural arachnodactyly (CCA)4, 5. The differences in expression and pathology have prompted the idea that the fibrillins have distinct but related functions[3]. Elucidating the molecular basis of these differences and overlaps will be critical for understanding the pathophysiology of fibrillin disorders.
Section snippets
Structure
The fibrillins have virtually superimposable structures[6]. Most of the molecule is made of cysteine-rich repeats homologous to motifs present in the epidermal growth factor precursor (EGF motif) and the LTBPs (TB motif) or unique to the fibrillins (Fib motif) (Fig. 1). The Fib motif is also known as the hybrid motif for it is hypothesized to have arose from the fusion of EGF and TB sequences.
The EGF motif consists of a central β-hairpin and a minor β-sheet at the C-terminus and the fold is
Synthesis and degradation
Microfibrils appear as thread-like filaments composed of beaded strings made of bundles of linear arms attached to the globular beads. The beaded strings probably represent pure fibrillin polymers; they subsequently assemble together with other components into thread-like filaments, which in turn give rise to macroaggregates with or without elastin (Fig. 2). Elastic fibers are present in tissues subjected to stretching and expansile forces, whereas microfibrils devoid of elastin are found in
Biological function
Fibrillin was believed to guide elastogenesis because microfibrils appear before tropoelastin deposition. The discovery of two differently expressed fibrillins prompted the idea that fibrillins- 1 and 2 are involved in tissue homeostasis and morphogenesis, respectively[3]. Recent gene targeting work in the mouse has corroborated half of this postulate[12].
Homozygous mutant mice produce shortened fibrillin-1 in less than the predicted amount, as result of an internal genomic deletion associated
Medical applications
The pathology of fibrillins is well-established, less so the pathogenesis. Fibrillin-1 mutations result in MFS, a multisystemic disorder with prominent manifestations in the skeleton, eye and the cardiovascular system[6]. Fibrillin-1 mutations fall into three functional categories. Amino acid substitutions which are expected to alter folding of EGF, TB and Fib modules; missense mutations which are predicted to inhibit the many related activities of calcium binding; internal deletions and
Acknowledgements
We indebted to Emilio Arteaga for preparing the illustrations and to Karen Johnson for typing the manuscript.
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