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Independent multimerization of Latent TGFβ Binding Protein-1 stabilized by cross-linking and enhanced by heparan sulfate

DOI: 10.1038/srep34347 DOI Help

Authors: Helen Troilo (Wellcome Trust Centre for Cell-Matrix Research) , Ruth 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) , Richard F. 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) , Cay M. 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) , Clair Baldock (The Wellcome Trust Centre for Cell-Matrix Research is within the School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 6

State: Published (Approved)
Published: September 2016
Diamond Proposal Number(s): 11534

Open Access Open Access

Abstract: 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.

Subject Areas: Biology and Bio-materials
Collaborations: Diamond Manchester

Instruments: B21-High Throughput SAXS

Other Facilities: ESRF

Added On: 04/11/2016 18:05

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srep34347.pdf

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