The N-terminal region of Fibrillin-1 mediates a bipartite interaction with LTBP1

Robertson, Ian B., Dias, Hans F., Osuch, Isabelle H., Lowe, Edward D., Jensen, Sacha A., Redfield, Christina, and Handford, Penny A. (2017) The N-terminal region of Fibrillin-1 mediates a bipartite interaction with LTBP1. Structure, 25 (8). 1208-1221.e5.

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Abstract

Fibrillin-1 (FBN1) mutations associated with Marfan syndrome lead to an increase in transforming growth factor β (TGF-β) activation in connective tissues resulting in pathogenic changes including aortic dilatation and dissection. Since FBN1 binds latent TGF-β binding proteins (LTBPs), the major reservoir of TGF-β in the extracellular matrix (ECM), we investigated the structural basis for the FBN1/LTBP1 interaction. We present the structure of a four-domain FBN1 fragment, EGF2-EGF3-Hyb1-cbEGF1 (FBN1E2cbEGF1), which reveals a near-linear domain organization. Binding studies demonstrate a bipartite interaction between a C-terminal LTBP1 fragment and FBN1E2cbEGF1, which lies adjacent to the latency-associated propeptide (LAP)/TGF-β binding site of LTBP1. Modeling of the binding interface suggests that, rather than interacting along the longitudinal axis, LTBP1 anchors itself to FBN1 using two independent epitopes. As part of this mechanism, a flexible pivot adjacent to the FBN1/LTBP1 binding site allows LTBP1 to make contacts with different ECM networks while presumably facilitating a force-induced/traction-based TGF-β activation mechanism.

Item ID: 60808
Item Type: Article (Research - C1)
ISSN: 1878-4186
Copyright Information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Funders: Medical Research Council (MRC), Biotechnologyand Biological Sciences Research Council, Arthritis Research UK (AR)
Projects and Grants: MRC grant MR/M009831/1, AR grant 20785
Date Deposited: 05 Nov 2019 00:00
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060112 Structural Biology (incl Macromolecular Modelling) @ 75%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060106 Cellular Interactions (incl Adhesion, Matrix, Cell Wall) @ 25%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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