Crystal Structure of the Frizzled-like Cysteine-rich Domain of the Receptor Tyrosine Kinase MuSK

By A. L. Stiegler, S. Burden, S. Hubbard. 2009

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Muscle-specific kinase (MuSK) is an essential receptor tyrosine kinase for establishment and maintenance of the neuromuscular junction (NMJ). Activation of MuSK by agrin, a neuronally derived heparan-sulfate proteoglycan, and LRP4, 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.

Subfields: Cardiology and Cardiovascular Medicine, Cell Biology, Molecular Biology

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Citations in the corpus

ECOD: An Evolutionary Classification of Protein Domains (2014, background): “FZ-CRD, as a mobile evolutionary module, has been found in other proteins such as the Smoothened receptor in Hedgehog signaling, secreted Frizzledrelated proteins (SFRPs), and receptor tyrosine kinases MuSK and ROR.”
Cysteine‐rich domains related to Frizzled receptors and Hedgehog‐interacting proteins (2012, background): “The CRD in Frizzled and Smoothened is a mobile evolutionary unit that has been found in other metazoan proteins, such as secreted Frizzled-related proteins (SFRPs) and certain receptor tyrosine kinases.(8,9) Recently, several domains distantly related to Frizzled CRDs, revealed by structural compari”