Abstract
The extracellular glycoprotein fibrillin-1 forms microfibrils that act as the template for elastic fibers. Most mutations in fibrillin-1 cause Marfan syndrome with severe cardiovascular and ocular symptoms, and tall stature. This is in contrast to mutations within a heparin-binding TB domain (TB5), which is downstream of the arg-gly-asp cell adhesion domain, which can cause Weill-Marchesani syndrome (WMS) or Acromicric (AD) and Geleophysic Dysplasias (GD). WMS is characterized by short limbs, joint stiffness and ocular defects, whilst fibrillin-1 AD and GD have severe short stature, joint defects and thickened skin. We previously showed that TB5 binds heparin. Here, we show that the corresponding region of fibrillin-2 binds heparin very poorly, highlighting a novel functional difference between the two isoforms. This finding enabled us to map heparin/heparan sulfate binding to two sites on fibrillin-1 TB5 using a mutagenesis approach. Once these sites were mapped, we were able to investigate whether disease-causing mutations in this domain disrupt binding to HS. We show that a WMS deletion mutant, and five AD and GD point mutants all have disrupted heparin binding to TB5. These data provide insights into the biology of fibrillins and the pathologies of WMS, AD and GD.
Highlights
Fibrillin-1 (FBN1) is a major glycoprotein of the extracellular matrix, which contains repeating calcium-binding epidermal growth factor-like domains interspersed with eightcysteine (TB) domains [1]
Heparin Binding by Fibrillin-1 and Fibrillin-2 TB5 Domains Previously, we showed that human fibrillin-1 contains a heparin binding site in TB5, which is close to the RGD-containing TB4 domain [6]
We focused on heparan sulfate (HS) binding to the TB5 domain, which we have previously shown to contribute to integrinmediated cellular interactions in a manner analogous with the fibronectin hepII region [9]
Summary
Fibrillin-1 (FBN1) is a major glycoprotein of the extracellular matrix, which contains repeating calcium-binding epidermal growth factor (cbEGF)-like domains interspersed with eightcysteine (TB) domains [1]. Two fibrillin-1 mutations cause autosomal dominant Weill-Marchesani syndrome (WMS), which is characterized by short stature, thick skin, stiff joints and ocular problems [14,15]. 16 point mutations have been reported in autosomal dominant Acromicric Dysplasia (AD) and Geleophysic Dysplasia (GD), which cause severe short stature, join defects and thickened skin [16]. It has remained unclear why mutations in TB5 cause WMS, AD or GD rather than Marfan syndrome
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