title: Modulation of agrin function by alternative splicing and Ca2+ binding.
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.
authors.affiliation: Department of Biophysical Chemistry, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. joerg.stetefeld@unibas.ch
authors.forename: Jörg
authors.initials: J
authors.lastname: Stetefeld
authors.forename: Andrei T
authors.initials: AT
authors.lastname: Alexandrescu
authors.forename: Mark W
authors.initials: MW
authors.lastname: Maciejewski
authors.forename: Margrit
authors.initials: M
authors.lastname: Jenny
authors.forename: Klara
authors.initials: K
authors.lastname: Rathgeb-Szabo
authors.forename: Therese
authors.initials: T
authors.lastname: Schulthess
authors.forename: Ruth
authors.initials: R
authors.lastname: Landwehr
authors.forename: Sabine
authors.initials: S
authors.lastname: Frank
authors.forename: Markus A
authors.initials: MA
authors.lastname: Ruegg
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kammerer
mesh_terms: D018171:Agrin / Q000235:genetics* / Q000378:metabolism*; D017398:Alternative Splicing / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D051381:Rats; D016415:Sequence Alignment
chemical_list: D018171:Agrin; D002118:Calcium