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Vol. 11, Issue 8, 2691-2704, August 2000
Binding
Proteins, LTBPs, Creates a Hydrophobic Interaction Surface for Binding
of Small Latent TGF-
Departments of Virology and Pathology, The Haartman Institute,
University of Helsinki, Helsinki, Finland
Transforming growth factor (TGF)-
s are secreted in large latent
complexes consisting of TGF-, its N-terminal latency-associated peptide (LAP) propeptide, and latent TGF- binding protein (LTBP). LTBPs are required for secretion and subsequent deposition of TGF-
into the extracellular matrix. TGF-1 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- by their 8-Cys repeats.
8-Cys repeat was found to interact with TGF-1
LAP by direct
cysteine bridging. LTBP-1 and LTBP-3 bound efficiently all TGF-
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-
binding motif was identified in the TGF- binding 8-Cys repeats.
Deletion of this motif in the 3rd 8-Cys repeat of LTBP-1
resulted in loss of TGF-LAP binding ability, while its inclusion
in non-TGF- binding 3rd 8-Cys repeat of LTBP-2 resulted
in TGF- binding. Molecular modeling of the 8-Cys repeats revealed a
hydrophobic interaction surface and lack of three stabilizing hydrogen
bonds introduced by the TGF- binding motif necessary for the
formation of the TGF-LAP - 8-Cys repeat complex inside the cells.
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