Specific sequence motif of 8-Cys repeats of TGF-β binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-β

J Saharinen, J Keski-Oja - Molecular biology of the cell, 2000 - Am Soc Cell Biol
J Saharinen, J Keski-Oja
Molecular biology of the cell, 2000Am Soc Cell Biol
Transforming growth factor (TGF)-βs are secreted in large latent complexes consisting of
TGF-β, its N-terminal latency-associated peptide (LAP) propeptide, and latent TGF-β binding
protein (LTBP). LTBPs are required for secretion and subsequent deposition of TGF-β into
the extracellular matrix. TGF-β1 associates with the 3rd 8-Cys repeat of LTBP-1 by LAP. All
LTBPs, as well as fibrillins, contain multiple 8-Cys repeats. We analyzed the abilities of
fibrillins and LTBPs to bind latent TGF-β by their 8-Cys repeats. 8-Cys repeat was found to …
Transforming growth factor (TGF)-βs are secreted in large latent complexes consisting of TGF-β, its N-terminal latency-associated peptide (LAP) propeptide, and latent TGF-β binding protein (LTBP). LTBPs are required for secretion and subsequent deposition of TGF-β into the extracellular matrix. TGF-β1 associates with the 3rd 8-Cys repeat of LTBP-1 by LAP. All LTBPs, as well as fibrillins, contain multiple 8-Cys repeats. We analyzed the abilities of fibrillins and LTBPs to bind latent TGF-β by their 8-Cys repeats. 8-Cys repeat was found to interact with TGF-β1•LAP by direct cysteine bridging. LTBP-1 and LTBP-3 bound efficiently all TGF-β isoforms, LTBP-4 had a much weaker binding capacity, whereas LTBP-2 as well as fibrillins -1 and -2 were negative. A short, specific TGF-β binding motif was identified in the TGF-β binding 8-Cys repeats. Deletion of this motif in the 3rd 8-Cys repeat of LTBP-1 resulted in loss of TGF-β•LAP binding ability, while its inclusion in non-TGF-β binding 3rd 8-Cys repeat of LTBP-2 resulted in TGF-β binding. Molecular modeling of the 8-Cys repeats revealed a hydrophobic interaction surface and lack of three stabilizing hydrogen bonds introduced by the TGF-β binding motif necessary for the formation of the TGF-β•LAP - 8-Cys repeat complex inside the cells.
Am Soc Cell Biol