Independent multimerization of Latent TGFβ Binding Protein-1 stabilized by cross-linking and enhanced by heparan sulfate.
TGFβ plays key roles in fibrosis and cancer progression, and latency is conferred by covalent linkage to latent TGFβ binding proteins (LTBPs). LTBP1 is essential for TGFβ folding, secretion, matrix localization and activation but little is known about its structure due to its inherent size and flexibility. Here we show that LTBP1 adopts an extended conformation with stable matrix-binding N-terminus, extended central array of 11 calcium-binding EGF domains and flexible TGFβ-binding C-terminus. Moreover we demonstrate that LTBP1 forms short filament-like structures independent of other matrix components. The termini bind to each other to facilitate linear extension of the filament, while the N-terminal region can serve as a branch-point. Multimerization is enhanced in the presence of heparin and stabilized by the matrix cross-linking enzyme transglutaminase-2. These assemblies will extend the span of LTBP1 to potentially allow simultaneous N-terminal matrix and C-terminal fibrillin interactions providing tethering for TGFβ activation by mechanical force.
The Wellcome Trust Centre for Cell-Matrix Research is within the School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
Helen
H
Troilo
The Wellcome Trust Centre for Cell-Matrix Research is within the School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
Ruth
R
Steer
The Wellcome Trust Centre for Cell-Matrix Research is within the School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
Richard F
RF
Collins
The Wellcome Trust Centre for Cell-Matrix Research is within the School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
Cay M
CM
Kielty
The Wellcome Trust Centre for Cell-Matrix Research is within the School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
Clair
C
Baldock
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