Crystal Structure of the Frizzled-Like Cysteine-Rich Domain of the Receptor Tyrosine Kinase MuSK |
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Authors: | Amy L Stiegler Steven J Burden |
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Institution: | 1 Structural Biology Program, Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA 2 Molecular Neurobiology Program, Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA 3 Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA |
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Abstract: | Muscle-specific kinase (MuSK) is an essential receptor tyrosine kinase for the establishment and maintenance of the neuromuscular junction (NMJ). Activation of MuSK by agrin, a neuronally derived heparan-sulfate proteoglycan, and LRP4 (low-density lipoprotein receptor-related protein-4), the agrin receptor, leads to clustering of acetylcholine receptors on the postsynaptic side of the NMJ. The ectodomain of MuSK comprises three immunoglobulin-like domains and a cysteine-rich domain (Fz-CRD) related to those in Frizzled proteins, the receptors for Wnts. Here, we report the crystal structure of the MuSK Fz-CRD at 2.1 Å resolution. The structure reveals a five-disulfide-bridged domain similar to CRDs of Frizzled proteins but with a divergent C-terminal region. An asymmetric dimer present in the crystal structure implicates surface hydrophobic residues that may function in homotypic or heterotypic interactions to mediate co-clustering of MuSK, rapsyn, and acetylcholine receptors at the NMJ. |
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Keywords: | MuSK muscle-specific kinase NMJ neuromuscular junction RTK receptor tyrosine kinase LRP4 low-density lipoprotein receptor-related protein-4 Ig immunoglobulin CRD cysteine-rich domain Fz-CRD Frizzled-like CRD Fz8 Frizzled-8 sFRP3 secreted Frizzled-related protein-3 PDB Protein Data Bank |
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