Two distinct regions of latency-associated peptide coordinate stability of the latent transforming growth factor-beta1 complex.

Abstract

Transforming growth factor-beta1 (TGF-beta1) is secreted as part of an inactive complex consisting of the mature dimer, the TGF-beta1 propeptide (latency-associated peptide (LAP)), and latent TGF-beta-binding proteins. Using in vitro mutagenesis, we identified the regions of LAP that govern the cooperative assembly and stability of the latent TGF-beta1 complex. Initially, hydrophobic LAP residues (Ile(53), Leu(54), Leu(57), and Leu(59)), which form a contiguous epitope on one surface of an amphipathic alpha-helix, interact with mature TGF-beta1 to form the small latent complex. TGF-beta1 binding is predicted to alter LAP conformation, exposing ionic residues (Arg(45), Arg(50), Lys(56), and Arg(58)) on the other side of the alpha-helix, which form the binding site for latent TGF-beta-binding proteins. The stability of the resultant large latent complex is dependent upon covalent dimerization of LAP, which is facilitated by key residues (Phe(198), Asp(199), Val(200), Leu(208), Phe(217), and Leu(219)) at the dimer interface. Significantly, genetic mutations in LAP (e.g. R218H) that cause the rare bone disorder Camurati-Engelmann disease disrupted dimerization and reduced the stability of the latent TGF-beta1 complex.

• Authors: Kelly L Walton, Yogeshwar Makanji, Justin Chen, Matthew C Wilce, Karen L Chan, David M Robertson, Craig A Harrison
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 22 Pg. 17029-37 (May 28 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20308061 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Conditioned
• Latent TGF-beta Binding Proteins
• Peptides
• Transforming Growth Factor beta
• Transforming Growth Factor beta1

Topics

• Amino Acid Sequence
• Biological Assay
• Camurati-Engelmann Syndrome (metabolism)
• Culture Media, Conditioned (pharmacology)
• Dimerization
• Extracellular Matrix (metabolism)
• Humans
• Latent TGF-beta Binding Proteins (chemistry)
• Molecular Sequence Data
• Mutation
• Peptides (chemistry)
• Protein Binding
• Protein Interaction Mapping (methods)
• Protein Structure, Tertiary
• Transforming Growth Factor beta (metabolism)
• Transforming Growth Factor beta1 (metabolism)