Activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 155351
Author(s) Scotton, P.; Bleckmann, D.; Stebler, M.; Sciandra, F.; Brancaccio, A.; Meier, T.; Stetefeld, J.; Ruegg, M. A.
Author(s) at UniBasel Rüegg, Markus A.
Year 2006
Title Activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin
Journal Journal of Biological Chemistry
Volume 281
Number 48
Pages / Article-Number 36835-45
Keywords Agrin/biosynthesis/*chemistry; *Alternative Splicing; Amino Acid Sequence; Animals; Binding Sites; Chickens; Dystroglycans/chemistry; Humans; Laminin/chemistry; Mice; Molecular Sequence Data; Muscles/*enzymology; RNA; Messenger/*metabolism; Receptor Protein-Tyrosine Kinases/*chemistry; Sequence Homology; Amino Acid
Mesh terms Agrin, chemistry; Alternative Splicing; Amino Acid Sequence; Animals; Binding Sites; Chickens; Dystroglycans, chemistry; Humans; Laminin, chemistry; Mice; Molecular Sequence Data; Muscles, enzymology; RNA, Messenger, metabolism; Receptor Protein-Tyrosine Kinases, chemistry; Sequence Homology, Amino Acid
Abstract Agrin induces the aggregation of postsynaptic proteins at the neuromuscular junction (NMJ). This activity requires the receptor-tyrosine kinase MuSK. Agrin isoforms differ in short amino acid stretches at two sites, called A and B, that are localized in the two most C-terminal laminin G (LG) domains. Importantly, agrin isoforms greatly differ in their activities of inducing MuSK phosphorylation and of binding to alpha-dystroglycan. By using site-directed mutagenesis, we characterized the amino acids important for these activities of agrin. We find that the conserved tripeptide asparagineglutamate-isoleucine in the eight-amino acid long insert at the B-site is necessary and sufficient for full MuSK phosphorylation activity. However, even if all eight amino acids were replaced by alanines, this agrin mutant still has significantly higher MuSK phosphorylation activity than the splice version lacking any insert. We also show that binding to alpha-dystroglycan requires at least two LG domains and that amino acid inserts at the A and the B splice sites negatively affect binding.
Publisher American Society for Biochemistry and Molecular Biology
ISSN/ISBN 0021-9258 ; 1083-351X
URL http://www.jbc.org/content/281/48/36835.full.pdf
edoc-URL http://edoc.unibas.ch/dok/A5258385
Full Text on edoc Restricted
Digital Object Identifier DOI 10.1074/jbc.M607887200
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/17012237
ISI-Number WOS:000242220800042
Document type (ISI) Journal Article
 
   

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