Structural and Functional Implications of Human Transforming Growth Factor β-Induced Protein, TGFBIp, in Corneal Dystrophies

Structure. 2017 Nov 7;25(11):1740-1750.e2. doi: 10.1016/j.str.2017.09.001. Epub 2017 Oct 5.


A major cause of visual impairment, corneal dystrophies result from accumulation of protein deposits in the cornea. One of the proteins involved is transforming growth factor β-induced protein (TGFBIp), an extracellular matrix component that interacts with integrins but also produces corneal deposits when mutated. Human TGFBIp is a multi-domain 683-residue protein, which contains one CROPT domain and four FAS1 domains. Its structure spans ∼120 Å and reveals that vicinal domains FAS1-1/FAS1-2 and FAS1-3/FAS1-4 tightly interact in an equivalent manner. The FAS1 domains are sandwiches of two orthogonal four-stranded β sheets decorated with two three-helix insertions. The N-terminal FAS1 dimer forms a compact moiety with the structurally novel CROPT domain, which is a five-stranded all-β cysteine-knot solely found in TGFBIp and periostin. The overall TGFBIp architecture discloses regions for integrin binding and that most dystrophic mutations cluster at both molecule ends, within domains FAS1-1 and FAS1-4.

Keywords: corneal dystrophy; crystal structure; cysteine-rich CROPT domain; extracellular matrix protein; fasciclin FAS1 domain; multi-domain protein; pathological mutants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cloning, Molecular
  • Corneal Dystrophies, Hereditary / genetics
  • Corneal Dystrophies, Hereditary / metabolism
  • Corneal Dystrophies, Hereditary / pathology
  • Crystallography, X-Ray
  • Extracellular Matrix Proteins / chemistry*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • HEK293 Cells
  • Humans
  • Integrins / chemistry*
  • Integrins / genetics
  • Integrins / metabolism
  • Models, Molecular
  • Mutation*
  • Protein Aggregates*
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Transforming Growth Factor beta / chemistry*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism


  • Extracellular Matrix Proteins
  • Integrins
  • Protein Aggregates
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • betaIG-H3 protein