5MS9

Solution structure of Human Fibrillin-1 EGF2-EGF3-Hybrid1-cbEGF1 four domain fragment

Summary for 5MS9

• Entry DOI: 10.2210/pdb5ms9/pdb
• NMR Information: BMRB: 19078
• Descriptor: Fibrillin-1, CALCIUM ION (2 entities in total)
• Functional Keywords: fibrillin egf hybrid extracellular, structural protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 18910.67

Authors

Robertson, I.B.,Redfield, C.,Handford, P.A. (deposition date: 2017-01-01, release date: 2017-08-09, Last modification date: 2024-10-23)

Primary citation

Robertson, I.B.,Dias, H.F.,Osuch, I.H.,Lowe, E.D.,Jensen, S.A.,Redfield, C.,Handford, P.A.
The N-Terminal Region of Fibrillin-1 Mediates a Bipartite Interaction with LTBP1.
Structure, 25:1208-1221.e5, 2017

PubMed 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 (FBN1), which reveals a near-linear domain organization. Binding studies demonstrate a bipartite interaction between a C-terminal LTBP1 fragment and FBN1, 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.

PubMed: 28669633
DOI: 10.1016/j.str.2017.06.003

Experimental method

SOLUTION NMR