The fibrillin‐marfan syndrome connection

Abstract

A few years ago no one would have suspected that the well-known disorder of connective tissue, Marfan syndrome, could be caused by mutations in a recently discovered extracellular component, fibrillin. Likewise, nobody would have predicted that fibrillin represents a small family of proteins that are associated with several phenotypically overlapping disorders. The fibrillins are integral constituents of the non-collagenous microfibrils, with an average diameter of 10 nm. These aggregates are distributed in the extracellular matrix of virtually every tissue. Microfibrillar bundles provide the external coating to elastin in elastic fibers, and serve an anchoring function in non-elastic tissues. At higher resolution, individual microfibrils have a "beads-on-a-string" appearance resulting from the head-to-tail polymerization of multiple fibrillin aggregates. Structurally, fibrillin contains a series of repeated sequences homologous to the epidermal growth factor calcium-binding motif. Characterization of fibrillin mutations in Marfan syndrome patients, together with the elucidation of the structure of the fibrillin proteins, have provided new insights, and raised new questions, about the function of the 10 nm microfibrils. For example, it is possible that the fibrillins, in addition to serving a structural function, might also be involved in regulating cellular activities and morphogenetic programs. It is fitting that the long search for the Marfan syndrome gene has brought a novel group of proteins to the forefront of extracellular matrix biology.

Bovine Latent Transforming Growth Factor β1-Binding Protein 2: Molecular Cloning, Identification of Tissue Isoforms, and Immunolocalization to Elastin-Associated Microfibrils

“…In this paper, we describe the cloning and partial characterization of a large, cysteine-rich protein from a bovine elastic tissue; the protein has structural similarities to the fibrillin family of matrix proteins (26,31,36) and to LTBP-1 (20,39), a protein which forms covalent complexes with the latent form of TGF-␤1 (27). Alignment of cDNA and encoded amino acid sequences indicated that the new protein has levels of similarity to human LTBP-1 of around 40% and to human fibrillins 1 and 2 of 20%.…”

“…Fibrillins are characterized by a primary structure consisting predominantly of cysteine-rich repeat motifs of two distinct types: (i) 6-cysteine repeats, which are similar to motifs found in epidermal growth factor (EGF) precursor and a range of other proteins (EGF-like repeats) (18,26,31), and (ii) 8-cysteine repeats, which until very recently had been identified in only one other protein, latent transforming growth factor-␤1 (TGF-␤1)-binding protein 1 (LTBP-1) (20,39). LTBP-1 forms soluble disulfide-bonded complexes with latent forms of TGF-␤s (27) and is considered important for the efficient secretion of these growth factors (28).…”

Expression of a mutant human fibrillin allele upon a normal human or murine genetic background recapitulates a Marfan cellular phenotype.

“…The abundance of cysteine-rich EGF-like and TGF-,31 bplike domains enables fibrillin monomers to participate in intramolecular as well as intermolecular interactions. Indeed, upon secretion into the extracellular matrix, fibrillin monomers rapidly form disulfide-bonded aggregates, which, in conjunction with other matrix components, lead to the formation of mature microfibrils (11,12). Rotary shadowing of these multimeric units reveals a beaded-string appearance, and it has been proposed that fibrillin monomers arrange in a head-to-tail fashion (8,13).…”

Different Susceptibilities of Fibulin‐1 and Fibulin‐2 to Cleavage by Matrix Metalloproteinases and Other Tissue Proteases

“…microfibril disorganization and severe pathological phenotypes (Ramirez et al, 1993;Kielty and Shuttleworth, 1995). An explanation for these observations was provided by NMR studies of synthetic fibrillin EGF modules which suggested that calcium is important for maintaining a rod-like shape of their tandem arrays, probably by binding to the interface between the modules (Handford et al, 1995;Wu et al, 1995).…”