Modulation of agrin function by alternative splicing and Ca2+ binding |
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Authors: | Stetefeld Jörg Alexandrescu Andrei T Maciejewski Mark W Jenny Margrit Rathgeb-Szabo Klara Schulthess Therese Landwehr Ruth Frank Sabine Ruegg Markus A Kammerer Richard A |
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Institution: | Department of Biophysical Chemistry, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. joerg.stetefeld@unibas.ch |
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Abstract: | The aggregation of acetylcholine receptors on postsynaptic membranes is a key step in neuromuscular junction development. This process depends on alternatively spliced forms of the proteoglycan agrin with "B-inserts" of 8, 11, or 19 residues in the protein's globular C-terminal domain, G3. Structures of the neural B8 and B11 forms of agrin-G3 were determined by X-ray crystallography. The structure of G3-B0, which lacks inserts, was determined by NMR. The agrin-G3 domain adopts a beta jellyroll fold. The B insert site is flanked by four loops on one edge of the beta sandwich. The loops form a surface that corresponds to a versatile interaction interface in the family of structurally related LNS proteins. NMR and X-ray data indicate that this interaction interface is flexible in agrin-G3 and that flexibility is reduced by Ca(2+) binding. The plasticity of the interaction interface could enable different splice forms of agrin to select between multiple binding partners. |
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