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© The Rockefeller University Press,
0021-9525/1999//1133 $5.00
The Journal of Cell Biology, Volume 146, Number 5,
, 1999 1133-1146
Original Article |
Distinct Domains of Musk Mediate Its Abilities to Induce and to Associate with Postsynaptic Specializations
sanesj{at}thalamus.wustl.edu
Agrin released from motor nerve terminals activates a muscle-specific receptor tyrosine kinase (MuSK) in muscle cells to trigger formation of the skeletal neuromuscular junction. A key step in synaptogenesis is the aggregation of acetylcholine receptors (AChRs) in the postsynaptic membrane, a process that requires the AChR-associated protein, rapsyn. Here, we mapped domains on MuSK necessary for its interactions with agrin and rapsyn. Myotubes from MuSK–/– mutant mice form no AChR clusters in response to agrin, but agrin-responsiveness is restored by the introduction of rat MuSK or a Torpedo orthologue. Thus, MuSK–/– myotubes provide an assay system for the structure–function analysis of MuSK. Using this system, we found that sequences in or near the first of four extracellular immunoglobulin-like domains in MuSK are required for agrin responsiveness, whereas sequences in or near the fourth immunoglobulin-like domain are required for interaction with rapsyn. Analysis of the cytoplasmic domain revealed that a recognition site for the phosphotyrosine binding domain–containing proteins is essential for MuSK activity, whereas consensus binding sites for the PSD-95/Dlg/ZO-1-like domain–containing proteins and phosphatidylinositol-3-kinase are dispensable. Together, our results indicate that the ectodomain of MuSK mediates both agrin- dependent activation of a complex signal transduction pathway and agrin-independent association of the kinase with other postsynaptic components. These interactions allow MuSK not only to induce a multimolecular AChR-containing complex, but also to localize that complex to a primary scaffold in the postsynaptic membrane.
Key Words: MuSK • acetylcholine receptors • neuromuscular junction • synapse • agrin
© 1999 The Rockefeller University Press
1.used in this paper: AChR, acetylcholine receptor; MASC, muscle-associated specificity component; MuSK, muscle-specific receptor tyrosine kinase; PDZ, PSD-95/Dlg/ZO-1-like; PTB, phosphotyrosine-binding; RATL, rapsyn-associated transmembrane linking molecule; rBTX, rhodamine-
-bungarotoxin
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