A model of FAS1 domain 4 of the corneal protein beta(ig)-h3 gives a clearer view on corneal dystrophies

Mol Vis. 2003 Sep 11:9:440-8.


Purpose: A progressive alteration of the cornea resulting in loss of transparency occurs in a set of hereditary diseases known as corneal dystrophies. A number of these dystrophies have been linked to mutations in the 5q31-linked gene product beta(ig)-h3 (TGFBIP, kerato-epithelin, MP78/70, RGD-CAP) although the mechanism by which the mutations cause disease remains unknown. Here we investigate the structural basis for the different corneal dystrophies caused by mutations of the beta(ig)-h3 protein. The integrin binding properties of beta(ig)-h3, described in several recent studies, have been analysed with respect to the beta(ig)-h3 structure.

Methods: The recently determined structure of a FAS1 domain pair from fasciclin I, an insect cell adhesion molecule and beta(ig)-h3 homologue, was used to generate a homology model of the beta(ig)-h3 FAS1 domain 4.

Results: The structural analysis of FAS1 domain 4 of beta(ig)-h3 predicts that the common mutations at positions 124 and 555 do not substantially alter the beta(ig)-h3 structure. In contrast, the rare missense mutations appear incompatible with the FAS1 fold. A number of residues implicated in integrin binding by previous mutagenesis are mostly buried and appear to have important structural roles.

Conclusions: The common mutations of beta(ig)-h3 at positions 124 and 555 are likely to affect protein-protein interactions directly, whereas the rare mutations are likely to cause misfolding of the protein within the cell. Previously identified integrin binding residues are unlikely to be directly involved in receptor binding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cell Adhesion Molecules, Neuronal / chemistry*
  • Cell Adhesion Molecules, Neuronal / genetics
  • Chromosomes, Human, Pair 5 / genetics
  • Cornea / chemistry*
  • Corneal Dystrophies, Hereditary / etiology*
  • Corneal Dystrophies, Hereditary / genetics
  • Corneal Dystrophies, Hereditary / pathology
  • Extracellular Matrix Proteins / chemistry*
  • Extracellular Matrix Proteins / genetics
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Mutation
  • Protein Binding
  • Protein Folding
  • Protein Interaction Mapping
  • Transforming Growth Factor beta / chemistry
  • Transforming Growth Factor beta / genetics


  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Transforming Growth Factor beta
  • fasciclin I
  • betaIG-H3 protein