title: Alternative RNA splicing that determines agrin activity regulates binding to heparin and alpha-dystroglycan.
abstract: Agrin is a component of the extracellular matrix that regulates aspects of neuromuscular junction differentiation. Identification of agrin-binding proteins has lead to the suggestion that alpha-dystroglycan is a muscle cell surface proteoglycan that mediates agrin activity. To further test this hypothesis, we have compared the ability of differentially active agrin isoforms to interact with a model component of proteoglycans, heparin, as well as with the putative proteoglycan alpha-dystroglycan. We demonstrate that an alternately spliced exon (encoding the sequence lysine, serine, arginine, lysine: Y site) is necessary for agrin-heparin interactions. We also show that alternate splicing at another site (Z site) dramatically affects interaction of alpha-dystroglycan with agrin. We propose a model in which multiple distinct domains of agrin interact with both protein and sugar moieties of alpha-dystroglycan. The isoform-specific binding of agrin to alpha-dystroglycan is consistent with a functional role for this interaction during synaptogenesis.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Stanford University, CA 94305, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Campanelli
authors.forename: G G
authors.initials: GG
authors.lastname: Gayer
authors.forename: R H
authors.initials: RH
authors.lastname: Scheller
mesh_terms: D018171:Agrin / Q000235:genetics* / Q000378:metabolism*; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D049030:Dystroglycans; D014644:Genetic Variation; D006493:Heparin / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018171:Agrin; D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D049030:Dystroglycans; D006493:Heparin