Abstract
Proteins from the LTBP/fibrillin family perform key structural and functional roles in connective tissues. LTBP1 forms the large latent complex with TGFβ and its propeptide LAP, and sequesters the latent growth factor to the extracellular matrix. Bioinformatics studies suggest the main structural features of the LTBP1 C-terminus are conserved through evolution. NMR studies were carried out on three overlapping C-terminal fragments of LTBP1, comprising four domains with characterised homologues, cbEGF14, TB3, EGF3 and cbEGF15, and three regions with no homology to known structures. The NMR data reveal that the four domains adopt canonical folds, but largely lack the interdomain interactions observed with homologous fibrillin domains; the exception is the EGF3-cbEGF15 domain pair which has a well-defined interdomain interface. 15N relaxation studies further demonstrate that the three interdomain regions act as flexible linkers, allowing a wide range of motion between the well-structured domains. This work is consistent with the LTBP1 C-terminus adopting a flexible “knotted rope” structure, which may facilitate cell matrix interactions, and the accessibility to proteases or other factors that could contribute to TGFβ activation.
Highlights
The human genome encodes four latent transforming growth factor-b (TGFb) binding proteins (LTBPs)
The glycine-aromatic motifs in EGF3, on the other hand, are highly conserved, suggesting a packing interaction may occur between EGF3 and cbEGF15
The data presented here demonstrate that the Cterminus of LTBP1 behaves like a ‘‘knotted rope’’ in solution, where the linkers either side of the TB3 domain act as the highly flexible ‘‘rope’’ allowing the TB3 domain and EGF3-cbEGF15 domain pair, to move freely relative to each other and the rest of LTBP1
Summary
The human genome encodes four latent transforming growth factor-b (TGFb) binding proteins (LTBPs). These are large extracellular proteins which contain variable numbers of epidermal growth factor-like (EGF), calcium-binding EGF (cbEGF) and ‘‘TGFb’’ binding protein-like (TB) domains, but all of which conform to a similar domain architecture (Figure 1). LTBPs are involved in facilitating the folding and secretion of TGFb from the cell [4], directing its deposition to the extracellular matrix (ECM) [5,6], and playing a role in its activation and release from the latent state [7,8]. LTBP1 forms covalent disulphide links via its second TB domain to the propeptides of TGFb 1, 2 and 3 (otherwise known as Latency Associated Propeptides (LAPs)) [9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
