Modulation of agrin function by alternative splicing and Ca2+ binding.
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.
Stetefeld
Jörg
J
Department of Biophysical Chemistry, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. joerg.stetefeld@unibas.ch
Alexandrescu
Andrei T
AT
Maciejewski
Mark W
MW
Jenny
Margrit
M
Rathgeb-Szabo
Klara
K
Schulthess
Therese
T
Landwehr
Ruth
R
Frank
Sabine
S
Ruegg
Markus A
MA
Kammerer
Richard A
RA
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
D018171:Agrin; D002118:Calcium