Fibrillin-integrin interactions in health and disease.
Human fibrillin-1 is the major structural protein of extracellular matrix 10-12 nm microfibrils. It has a disulfide-rich modular organization which consists primarily of cbEGF (Ca(2+)-binding epidermal growth factor-like) domains and TB (transforming growth factor beta-binding protein-like) domains. TB4 contains an RGD (Arg-Gly-Asp) integrin-binding motif. The atomic structure of this region has been solved by X-ray crystallography and shows the TB4 and flanking cbEGF domains to be arranged as a tetragonal pyramid with N- and C-termini exposed at opposite ends of the fragment. The RGD integrin-binding motif is located within a flexible loop. We have used a variety of biophysical, biochemical and cell biology methods to investigate the molecular properties of integrin-fibrillin-1 interactions and have demonstrated that recombinant fibrillin-1 domain fragments mediate binding to integrins alphaVbeta3, alpha5beta1 and alphaVbeta6. Integrin alphaVbeta3 is a high-affinity fibrillin-1 receptor (K(d) approximately 40 nM), whereas integrins alphaVbeta6 and alpha5beta1 show moderate-affinity (K(d) approximately 450 nM) and low-affinity (K(d) >1 microM) binding respectively. Different patterns of alpha5beta1 distribution are seen when human keratinocytes and fibroblasts are plated on to fibrillin domain fragments compared with those seen for fibronectin, suggesting that fibrillin may cause a lesser degree or different type of intracellular signalling. A number of disease-causing mutations which affect the TB4 domain have been identified. These are being investigated for their effects on integrin binding and/or changes in intramolecular structure.
Jovanović
Jelena
J
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
Iqbal
Sarah
S
Jensen
Sacha
S
Mardon
Helen
H
Handford
Penny
P
D000818:Animals; D018360:Crystallography, X-Ray; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism; D054392:Adipokines
D000071838:Fibrillin-1; D000071837:Fibrillins; D016023:Integrins; D008840:Microfilament Proteins; D009842:Oligopeptides; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C047981:arginyl-glycyl-aspartic acid