Abstract
We have defined the molecular basis of cell adhesion to fibrillin-1, the major structural component of extracellular microfibrils that are associated with elastic fibres. Using human dermal fibroblasts, and recombinant domain swap fragments containing the Arg-Gly-Asp motif, we have demonstrated a requirement for upstream domains for integrin-alpha(5)beta(1)-mediated cell adhesion and migration. An adjacent heparin-binding site, which supports focal adhesion formation, was mapped to the fibrillin-1 TB5 motif. Site-directed mutagenesis revealed two arginine residues that are crucial for heparin binding, and confirmed their role in focal adhesion formation. These integrin and syndecan adhesion motifs juxtaposed on fibrillin-1 are evolutionarily conserved and reminiscent of similar functional elements on fibronectin, highlighting their crucial functional importance.
Highlights
Fibrillin-1 is a large extracellular matrix glycoprotein and the major constituent of fibrillin-rich microfibrils (Kielty et al, 2005; Kielty, 2006)
We have shown that integrins ␣v3 and ␣51 can both bind to recombinant fibrillin-1 fragments expressed in a mammalian system, in a cell-specific manner (Bax et al, 2003)
We have previously shown that fibrillin-1 interacts with cells through integrins ␣51 and ␣v3, in an RGD-dependent manner (Bax et al, 2003)
Summary
Fibrillin-1 is a large extracellular matrix glycoprotein and the major constituent of fibrillin-rich microfibrils (Kielty et al, 2005; Kielty, 2006). It contains 47 epidermal growth factor (EGF) domains, of which 43 are calcium binding (cbEGF)-like domains, and 7 eight-cysteine-containing TB motifs (Pereira et al, 1993) (Fig. 1). It has a single Arg-Gly-Asp (RGD) cell adhesion motif within the fourth TB repeat (TB4), which is surrounded by polar, charged amino acids and likely to be solvent exposed. The TB4 RGD motif is conserved in fibrillin-2 (Zhang et al, 1994)
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