Molecules in focus
The fibrillins

https://doi.org/10.1016/S1357-2725(98)00109-5Get rights and content

Abstract

Fibrillins 1 and 2 are the main constituents of the extracellular microfibrils responsible for the biomechanical properties of most tissues and organs. They are cysteine-rich glycoproteins predominantly made of multiple repeats homologous to the calcium-binding epidermal growth factor module, and are translated as precursor proteins cleaved by furine/PACE-like activities. Fibrillins polymerize extracellularly as parallel bundles of head-to-tail monomers. Binding to calcium rigidifies the structure of the monomers and the supramolecular organization of the macroaggregates. Fibrillin-1 mutations result in the pleiotropic manifestations of Marfan syndrome, and fibrillin-2 alterations cause the overlapping phenotype of congenital contractural arachnodactyly. It is hypothesized that fibrillin-2 guides elastogenesis, whereas fibrillin-1 provides force-bearing structural support. Gene targeting work in the mouse is shedding new light on their distinct and overlapping contributions to tissue morphogenesis and homeostasis. It is also providing an animal model in which to test therapies aimed at reducing hemodynamic stress and the collapse of the aortic matrix during dissecting aneurysm.

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.

References (13)

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    Citation Excerpt :

    Study of two FBN1 missense mutations, C1977Y and C1977R in the cb-EGF domain, cause fibrillin-1 to have increased susceptibility for proteolysis of the mutant fragment, which suggests that disruption of these calcium binding EGF-like domains alters fibrillin-1 such that proteases can degrade it more easily.43 Cb-EGF domains also mediate interactions between fibrillin and cells via integrin αVβ3 binding to fibrillin, and interactions among monomers favouring lateral packing of microfibrils.44,45 As described herein, fibrillin is a critical component of the elastin-contractile unit and the mutations in FBN1 either disrupt deposition of fibrillin into microfibrils that surround the elastin fibre or decrease the amount of fibrillin available to form microfibrils due to haploinsufficiency.

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