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

• Published in: Structure (London) 2017-11, Vol.25 (11), p.1740-1750.e2
• Main Authors: García-Castellanos, Raquel, Nielsen, Nadia Sukusu, Runager, Kasper, Thøgersen, Ida B., Lukassen, Marie V., Poulsen, Ebbe T., Goulas, Theodoros, Enghild, Jan J., Gomis-Rüth, F. Xavier
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Binding Sites; Cloning, Molecular; Corneal Dystrophies, Hereditary - genetics; Corneal Dystrophies, Hereditary - metabolism; Corneal Dystrophies, Hereditary - pathology; corneal dystrophy; crystal structure; Crystallography, X-Ray; cysteine-rich CROPT domain; extracellular matrix protein; Extracellular Matrix Proteins - chemistry; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; fasciclin FAS1 domain; Gene Expression; Genetic Vectors - chemistry; Genetic Vectors - metabolism; HEK293 Cells; Humans; Integrins - chemistry; Integrins - genetics; Integrins - metabolism; Models, Molecular; multi-domain protein; Mutation; pathological mutants; 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
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2017.09.001

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. [Display omitted] •Transforming growth factor β-induced protein (TGFBIp) is a corneal matrix component•Mutated TGFBIp produces deposits in the cornea that lead to corneal dystrophies•TGFBIp is banana shaped, spans 120 Å, and comprises one CROPT and four FAS1 domains•Most dystrophic mutations cluster within terminal domains FAS1-1 and FAS1-4 García-Castellanos et al. report the structure of transforming growth factor β-induced protein (TGFBIp), a corneal component. When mutated, TGFBIp accumulates and causes corneal dystrophies and vision impairment. The elongated structure of TGFBIp comprises one CROPT and four FAS1 domains, and most dystrophic mutations cluster within terminal domains FAS1-1 and FAS1-4.