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The laminin-binding domain of agrin is structurally related to N-TIMP-1

Abstract

Agrin is the key organizer of postsynaptic differentiation at the neuromuscular junction. This organization activity requires the binding of agrin to the synaptic basal lamina. Binding is conferred by the N-terminal agrin (NtA) domain, which mediates a high-affinity interaction with the coiled coil domain of laminins. Here, we report the crystal structure of chicken NtA at 1.6 Å resolution. The structure reveals that NtA harbors an oligosaccharide/oligonucleotide-binding fold with several possible sites for the interaction with different ligands. A high structural similarity of NtA with the protease inhibition domain in tissue inhibitor of metalloproteinases-1 (TIMP-1) supports the idea of additional functions of agrin besides synaptogenic activity.

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Figure 1: Structure of the NtA domain.
Figure 2: NtA is structurally related to N-TIMP-1.
Figure 3: Stereo view of the section of the final 2.7 Å resolution 2Fo − Fc electron density map (blue; 1 σ contour level) around the N-terminal segment of the NtA structure in complex (starting with Cys 2).
Figure 4: Electrostatic surface representation of the complexed NtA domain.

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Acknowledgements

We thank N.J. Bulleid and G. Orriss for critical reading of the manuscript. This work was supported by the Swiss National Science Foundation to J.E.

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Correspondence to Jürgen Engel.

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Stetefeld, J., Jenny, M., Schulthess, T. et al. The laminin-binding domain of agrin is structurally related to N-TIMP-1. Nat Struct Mol Biol 8, 705–709 (2001). https://doi.org/10.1038/90422

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